CN105121445A - 5H-chromeno[3,4-c]pyridines as inhibitors of adaptor associated kinase 1 (AAK1) - Google Patents
5H-chromeno[3,4-c]pyridines as inhibitors of adaptor associated kinase 1 (AAK1) Download PDFInfo
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- 0 C*CNC(*)*(C)C(C)* Chemical compound C*CNC(*)*(C)C(C)* 0.000 description 6
- NVRXDSNZKDFZSQ-QGZVFWFLSA-N CC(C)C[C@H](C(Nc(cc1)cc2c1-c1ccncc1C(C)(C)O2)=O)N Chemical compound CC(C)C[C@H](C(Nc(cc1)cc2c1-c1ccncc1C(C)(C)O2)=O)N NVRXDSNZKDFZSQ-QGZVFWFLSA-N 0.000 description 2
- UHWGHBXXNNKYMB-UHFFFAOYSA-N CC(C)(C#C)Oc1c(C=O)ccc(Br)c1 Chemical compound CC(C)(C#C)Oc1c(C=O)ccc(Br)c1 UHWGHBXXNNKYMB-UHFFFAOYSA-N 0.000 description 1
- HUAFUIUKYGGEGD-UHFFFAOYSA-N CN(C)CC(Nc(cc1)cc(OC2)c1-c1c2cncc1)=O Chemical compound CN(C)CC(Nc(cc1)cc(OC2)c1-c1c2cncc1)=O HUAFUIUKYGGEGD-UHFFFAOYSA-N 0.000 description 1
- SZPKROSXWRBYQI-UHFFFAOYSA-N COC(c1cnccc1Br)=O Chemical compound COC(c1cnccc1Br)=O SZPKROSXWRBYQI-UHFFFAOYSA-N 0.000 description 1
- MPBKMQDHVHDICH-UHFFFAOYSA-N N#CCC(Nc(cc1)cc(OC2)c1-c1c2cncc1)=O Chemical compound N#CCC(Nc(cc1)cc(OC2)c1-c1c2cncc1)=O MPBKMQDHVHDICH-UHFFFAOYSA-N 0.000 description 1
- DYRMBQRXOMOMNW-UHFFFAOYSA-N O=Cc1cnccc1Cl Chemical compound O=Cc1cnccc1Cl DYRMBQRXOMOMNW-UHFFFAOYSA-N 0.000 description 1
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Abstract
The present disclosure is generally directed to compounds which can inhibit AAKl (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAKl.
Description
The cross reference of related application
This application claims the rights and interests of the U.S. Provisional Patent Application 61/768051 that on February 22nd, 2013 submits to, it is all incorporated to the present invention by way of reference.
Technical field
The present invention relates generally to the compound that can suppress to connect albumen associated kinase 1 (adaptorassociatedkinase1, AAK1), the composition comprising above-claimed cpd and suppresses the method for AAK1.
Background technology
Connect the member of the Ark1/Prk1 family that albumen associated kinase 1 (AAK1) is serine/threonine kinase.AAK1mRNA exists with the two kinds of shear-forms being called as short-form and microscler formula.Microscler formula accounts for leading and expresses (HendersonandConner, Mol.Biol.Cell.2007,18,2698-2706) at brain and heart camber.AAK1 to be enriched in synaptosomal preparation (synaptosomalpreparation) and to locate altogether with cell endocytic structure in cultured cells.AAK1 regulates clathrin (clatherin) coated endocytosis, and it is process important in synaptic vesicle recycle and receptor-mediated cell endocytic.AAK1 and AP2 mixture combines, the allos tetramer that this mixture is connected with clathrin coating for making acceptor load (cargo).The combination of clathrin and AAK1 stimulates AAK1 kinase activity (Conneret.al., Traffic2003,4,885-890; Jacksonet.al., J.Cell.Biol.2003,163,231-236).The mu-2 subunit of AAK1 phosphorylation AP-2, it promotes that the sorting block (sortingmotif) containing tyrosine on mu-2 and load acceptor combines (Ricottaet.al., J.CellBio.2002,156,791-795; ConnerandSchmid, J.CellBio.2002,156,921-929).Mu2 phosphorylation is taken in optional for acceptor, but phosphorylation improves the efficiency (Motelyet.al., Mol.Biol.Cell.2006,17,5298-5308) of internalization.
AAK1 has been accredited as the inhibitor of neuregulin-1 in PC12 cell/ErbB4 intracellular signaling.The gene silencing of leading via mediated rnai or make AAK1 express the enhancing losing the spinous process hyperplasia (outgrowth) causing neuregulin-1 to be induced with kinase inhibitor K252a (its suppress AAK1 kinase activity) process.These process cause ErbB4 to express to be increased and ErbB4 cumulative rises in plasma membrane or near plasma membrane (Kuaiet.al., ChemistryandBiology2011,18,891-906).NRG1 and ErbB4 is (putative) schizophrenia sensitive gene (susceptibilitygene) (Buonanno, BrainRes.Bull.2010,83,122-131) of presumption.SNP in two kinds of genes relevant with phenotype in multiple schizophrenia (Greenwoodet.al., Am.J.Psychiatry2011,168,930-946).Neuregulin 1 and ErbB4KO mouse model have shown the relevant metamorphosis of schizophrenia and behavior phenotype (Jaaro-Peledet.al., SchizophreniaBulletin2010,36,301-313; Wenet.al., Proc.Natl.Acad.Sci.USA.2010,107,1211-1216).In addition, single nucleotide polymorphism (polymorphism) relevant with Parkinsonian age of onset (Latourelleet.al., BMCMed.Genet.2009,10,98) in the intron of AAK1 gene.These results show to suppress AAK1 activity to can be used for treating cognitive defect (cognitivedeficit) in schizophrenia (schizophrenia), schizophrenia, Parkinson's disease (Parkinson ' sdisease), neurogenic pain (neuropathicpain), Bipolar Disorder (bipolardisorder) and alzheimer's disease (Alzheimer ' sdisease).
Summary of the invention
In a first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof
Wherein:
R
1and R
2independently selected from hydrogen, C
3-C
6cycloalkyl and C
1-C
3alkyl, wherein said C
1-C
3alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, amino, cyano group, two (C
1-C
3alkyl) amino, halogen and hydroxyl; Or
R
1and R
2be oxo together;
R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, amino, optionally replacement have C
1-C
3the C of alkyl or cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl, C
1-C
3alkyl-Y and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, aryl, cyano group, two (C
1-C
3alkyl) amino, halogen, C
1-C
3haloalkylamino, C
1-C
3haloalkylcarbonylamino, hydroxyl ,-NR
xr
yand C
3-C
8cycloalkyl, wherein said cycloalkyl optionally replaces further one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, amino, aryl, aryl C
1-C
3alkyl, halogen, C
1-C
3haloalkyl, C
1-C
3haloalkylamino and hydroxyl;
R
4be selected from hydrogen, C
1-C
3alkoxyl group, C
1-C
3alkoxycarbonyl amino, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkyl-carbonyl-amino, amino, arylamino, aryl-amino-carbonyl, C
3-C
6cycloalkyl amino, C
3-C
6cycloalkyl amino carbonyl, C
3-C
6cycloalkyl oxy, halogen, C
1-C
3halogenated alkoxy, C
1-C
3haloalkyl, C
2-C
3haloalkylamino, C
2-c
3haloalkylcarbonylamino and hydroxyl;
R
5be selected from hydrogen, C
1-C
3alkyl, cyano group, C
3cycloalkyl and halogen;
R
xand R
ythe 3-6 ring optionally replacing and have oxo is formed together with connecting their nitrogen-atoms; And
Y is selected from
Wherein R
6be selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl and C
1-C
6alkyl-carbonyl;
N is 0,1,2 or 3;
Each R
7independently selected from hydrogen, C
1-C
6alkyl, aryl, aryl C
1-C
3alkyl, C
3-C
6cycloalkyl, halogen and C
1-C
3haloalkyl;
Each R
8independently selected from hydrogen, C
1-C
3alkoxyl group and hydroxyl; And
R
9and R
10separately for hydrogen or form oxo group together.
In the first embodiment of first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
9and R
10form oxo group together.In the second embodiment of first aspect, R
9and R
10be hydrogen and R separately
5for hydrogen.In the 3rd embodiment, R
9and R
10form oxo group together, R
5for hydrogen, and R
4be selected from hydrogen and C
1-C
3alkyl-carbonyl-amino.In the 4th embodiment, R
9and R
10form oxo group together, R
5for hydrogen, and R
4for hydrogen.
In the 5th embodiment of first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, R
9and R
10form oxo group together, R
1and R
2independently selected from hydrogen and C
1-C
3alkyl, or R
1and R
2be oxo together.
In the 6th embodiment of first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, wherein R
9and R
10form oxo group together, R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, optionally replacement have the C of cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces has one to be selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, cyano group, two (C
1-C
3alkyl) amino, hydroxyl and-NR
xr
y; Wherein R
xand R
y5 rings optionally replacing and have oxo are formed together with connecting their nitrogen-atoms.
In the 7th embodiment of first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, wherein:
R
1and R
2independently selected from hydrogen and C
1-C
3alkyl, or R
1and R
2be oxo together;
R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, optionally replacement have the C of cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces has one to be selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, cyano group, two (C
1-C
3alkyl) amino, hydroxyl and-NR
xr
y; Wherein R
xand R
y5 rings optionally replacing and have oxo are formed together with connecting their nitrogen-atoms;
R
4be selected from hydrogen and C
1-C
3alkyl-carbonyl-amino;
R
5for hydrogen; And
R
9and R
10form oxo group together.
In second aspect, the invention provides composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof of survival dose, and pharmaceutical carrier.
In a third aspect, the invention provides and suppress to connect the active method of albumen associated kinase 1 (AAK1), it comprises makes AAK1 contact with formula (I) compound or pharmaceutically acceptable salt thereof.
In fourth aspect, the invention provides treatment or dispose by the active disease of mediation of AAK1 or the method for illness, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof to the patient's drug treatment significant quantity having these needs.In the first embodiment of fourth aspect, described disease or illness are selected from alzheimer's disease, Bipolar Disorder, pain, Parkinson's disease and schizophrenia.In the second embodiment of fourth aspect, described pain is neurogenic pain.In the 3rd embodiment of fourth aspect, described neurogenic pain is fibromyalgia (fibromyalgia) or peripheral neuropathy (peripheralneuropathy).
In another aspect, the invention provides formula (II) compound or pharmaceutically acceptable salt thereof
Wherein:
R
1and R
2independently selected from hydrogen, C
3-C
6cycloalkyl and C
1-C
3alkyl, wherein said C
1-C
3alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, amino, cyano group, two (C
1-C
3alkyl) amino, halogen and hydroxyl; Or
R
1and R
2be oxo together;
R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, amino, optionally replacement have C
1-C
3the C of alkyl or cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl, C
1-C
3alkyl-Y and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, aryl, cyano group, two (C
1-C
3alkyl) amino, halogen, C
1-C
3haloalkylamino, C
1-C
3haloalkylcarbonylamino, hydroxyl ,-NR
xr
yand C
3-C
8cycloalkyl, wherein said cycloalkyl optionally replaces further one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, amino, aryl, aryl C
1-C
3alkyl, halogen, C
1-C
3haloalkyl, C
1-C
3haloalkylamino and hydroxyl;
R
4be selected from hydrogen, C
1-C
3alkoxyl group, C
1-C
3alkoxycarbonyl amino, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkyl-carbonyl-amino, amino, arylamino, aryl-amino-carbonyl, C
3-C
6cycloalkyl amino, C
3-C
6cycloalkyl amino carbonyl, C
3-C
6cycloalkyl oxy, halogen, C
1-C
3halogenated alkoxy, C
1-C
3haloalkyl, C
2-C
3haloalkylamino, C
2-c
3haloalkylcarbonylamino and hydroxyl;
R
5be selected from hydrogen, C
1-C
3alkyl, cyano group, C
3cycloalkyl and halogen;
R
xand R
ythe 3-6 ring optionally replacing and have oxo is formed together with connecting their nitrogen-atoms; And
Y is selected from
Wherein R
6be selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl and C
1-C
6alkyl-carbonyl;
N is 0,1,2 or 3;
Each R
7independently selected from hydrogen, C
1-C
6alkyl, aryl, aryl C
1-C
3alkyl, C
3-C
6cycloalkyl, halogen and C
1-C
3haloalkyl; And
Each R
8independently selected from hydrogen, C
1-C
3alkoxyl group and hydroxyl.
Other side of the present invention can comprise the appropriate combination of the embodiment disclosed in the application.
Other side and embodiment are found in the description that the application provides.
Embodiment
Part of the present invention shows resistance discovery based on AAK1 knock out mice to pain.The final research finding AAK1 inhibitor, comprise their compoistion and method of use is facilitated in this discovery.
In this application, description of the invention should be understood to the rule and the principle that meet chemical bonding.In some cases, removable hydrogen atom to hold substituting group on any given position.
Should be understood that, the compound that the present invention is contained is suitably stablize the compound being used as medicament.
Specify that the definition of any substituting group of specific location in the molecule or the definition of variable and its other position in this molecule has nothing to do.Such as, when n is 2, two R
6group may be the same or different separately.
Following term used in this specification sheets has indicated implication:
The all patents quoted in this specification sheets, patent application and reference are all introduced the application as a reference.In the case of inconsistencies, be as the criterion with the present invention's (comprising definition).
Unless the context clearly determines otherwise, the application's singulative used comprises plural.
In some cases, the carbonatoms in any special groups was shown before describing group.Such as, term " C
1-6alkyl " represent containing an alkyl to six carbon atom.If there are these to specify, then it replaces other definition contained all in the application.
The application's term " alkoxyl group " used refers to the alkyl be connected with parent molecular moiety via Sauerstoffatom.
The application's term " alkoxyalkyl " used refers to replace have one, the alkyl of two or three alkoxyl groups.
The application's term " Alkoxyalkylamino " used refers to that wherein R is the-NHR of alkoxyalkyl.
The application's term " alkoxy carbonyl " used refers to the alkoxyl group be connected with parent molecular moiety via carbonyl.
The application's term " alkoxycarbonyl amino " used refers to that wherein R is the-NHR of alkoxy carbonyl.
The application's term " alkyl " used refers to the group derived from straight or branched stable hydrocarbon.
The application's term " alkylamino " used refers to that wherein R is the-NHR of alkyl.
The application's term " alkyl-carbonyl " used refers to the alkyl be connected with parent molecular moiety via carbonyl.
The application's term " alkyl-carbonyl-amino " used refers to that wherein R is the-NHR of alkyl-carbonyl.
The application's term " alkynyl " used refers to the straight or branched group containing at least one carbon-to-carbon triple bond.
The application's term " amino " used refers to-NH
2.
The application's term " amino-sulfonyl " used refers to-SO
2nH
2.
The application's term " aryl " used refers to that phenyl or wherein one or two ring are the bicyclic condensed loop systems of phenyl.Bicyclic condensed loop systems is formed by with the quaternary phenyl that extremely hexa-atomic aromatics or non-aromatic carbocycle condense.Aryl of the present invention can be connected with parent molecular moiety via commutable carbon atom any in group.The representative example of aryl includes but not limited to indanyl, indenyl, naphthyl, phenyl and tetralyl.
The application's term " arylalkyl " used refers to replace have one, the alkyl of two or three aryl.
The application's term " arylamino " used refers to that wherein R is the-NHR of aryl.
The application's term " aryl carbonyl " used refers to the aryl be connected with parent molecular moiety via carbonyl.
The application's term " aryl-amino-carbonyl " used refers to that wherein R is the-NHR of aryl carbonyl.
The application's term " carbonyl " used refer to-C (O)-.
The application's term " cyano group " used refers to-CN.
The application's term " cycloalkyl " used refers to have 0 heteroatomic saturated monocyclic hydrocarbon ring systems.The representative example of cycloalkyl includes but not limited to cyclopropyl, cyclopentyl and cyclohexyl.
The application's term " cycloalkyl amino " used refers to that wherein R is the-NHR of cycloalkyl.
The application's term " naphthene base carbonyl " used refers to the cycloalkyl be connected with parent molecular moiety via carbonyl.
The application's term " cycloalkyl amino carbonyl " used refers to that wherein R is the-NHR of naphthene base carbonyl.
The application's term " cycloalkyl oxy " used refers to the cycloalkyl be connected with parent molecular moiety via Sauerstoffatom.
The application's term " dialkyl amido " used refers to that wherein each R is the-NR of alkyl
2.Two R group may be the same or different.
The application's term " halogen " used refers to Br, Cl, F and/or I.
The application's term " halogenated alkoxy " used refers to the haloalkyl be connected with parent molecular moiety via Sauerstoffatom.
The application's term " haloalkyl " used refer to the alkyl that replaces by one, two, three or four halogen atom.
The application's term " haloalkylamino " used refers to that wherein R is the-NHR of haloalkyl.
The application's term " halogenated alkyl carbonyl " used refers to the haloalkyl be connected with parent molecular moiety via carbonyl.
The application's term " Haloalkylcarbonylamino " used refers to that wherein R is the-NHR of halogenated alkyl carbonyl.
The application's term " hydroxyl " used refers to-OH.
Asymmetric center can be there is in the compounds of this invention.Should be understood that, all stereochemistry heterogeneous forms or their mixture with the ability suppressing AAK1 are contained in the present invention.The individual stereoisomers of compound can be prepared with synthesis mode by the marketable material containing chiral centre, or by the mixture preparing enantiomerism product be then separated (mixture being such as converted into diastereomer be then separated recrystallization, use chromatographic technique or on chiral chromatographic column, be directly separated enantiomer) prepare.Specific stereochemical initial compounds is commercially available or prepares by technology known in the art and split.
Some compound of the present invention can also separable different structural stability form exist.Torsion asymmetry (such as due to steric hindrance or ring strain) owing to the restricted rotation of asymmetric singly-bound can allow to be separated different conformer.The present invention includes often kind of configurational isomer or their mixture of these compounds.
Term " the compounds of this invention " and equivalents are intended to contain formula (I) compound and medicinal enantiomer, diastereomer and salt.Similarly, if context allows, then mention that intermediate is intended to contain their salt.
This invention is intended to all isotropic substances comprising the atom existed in the compounds of this invention.Isotropic substance comprises and has same atoms ordinal number but those atoms with different mass number.Do not limited by the mode of generally illustrating, the isotropic substance of hydrogen comprises deuterium and tritium.The isotropic substance of carbon comprises
13c and
14c.Isotope-labeled the compounds of this invention generally by routine techniques well known by persons skilled in the art or by with method similar described in the application, use applicable isotope-labeled reagent to substitute the unlabelled reagent used in addition and prepare.Above-claimed cpd can have multiple potential purposes, such as, measuring in biologic activity as standard substance and reagent.When stable isotope, above-claimed cpd can have the potential advantageously improveing biology, pharmacology or pharmacokinetic property.
The compounds of this invention can exist by acceptable salt." pharmaceutical salts " of the application's term used represents solubilized or is scattered in salt or the zwitterionic form of the compounds of this invention in water or oil, it is suitable for the contact tissue of patient and without excessive toxicity, stimulation, anaphylaxis or other problem or complication within the scope of rational medical judgment, with rational benefit/risk than conforming to and be effective for the purposes desired by it.Described salt can during final abstraction and purification compound or respectively by making suitable nitrogen-atoms and suitable acid-respons prepare.Representative acid salt comprises acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, dihydrobromide, dihydrochloride, two hydriodates, glycerophosphate, Hemisulphate, enanthate, hexanoate, formate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate, lactic acid salt, maleate, sym-toluenesulfonic acid salt, mesylate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, embonate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.The example that can be used for the acid forming acceptable addition salt comprises mineral acid such as hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid and organic acids as oxalic acid, toxilic acid, succsinic acid and Citric Acid.
Base addition salt can final be separated and during compound purifying by making carboxyl and suitable alkali or preparing with ammonia or organic primary amine, secondary amine or reactive tertiary amine, described alkali is the oxyhydroxide of such as metallic cation, carbonate or supercarbonate.The positively charged ion of pharmaceutical salts comprises lithium, sodium, potassium, calcium, magnesium and aluminium cations and nontoxic quaternary ammonium cation such as ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine, Tributylamine, pyridine, N, accelerine, N-methyl piperidine, N-methylmorpholine, dicyclohexyl amine, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N, N-dibenzyl phenylethylamine and N, N '-dibenzyl-ethylenediamin.Other the representative organic amine being applicable to be formed base addition salt comprises quadrol, thanomin, diethanolamine, piperidines and piperazine.
One embodiment of the invention contain the method that in vitro and in vivo suppresses to connect albumen associated kinase 1 (AAK1), and it comprises makes AAK1 and formula I or its acceptable salt thereof.
When treat formula (I) compound of significant quantity and their pharmaceutical salts can chemical feedstocks form administration be used for the treatment of time, pharmaceutical compositions can provide activeconstituents.Therefore, present invention also offers pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers, thinner or the vehicle for the treatment of significant quantity.
Unless otherwise stated, " the treatment significant quantity " of compound for being enough to the amount providing treatment benefit or delay or minimize one or more symptoms relevant with described disease or symptom in treatment or disposal disease or symptom.The amount of the therapeutic efficiency improving overall therapeutic, reduce or avoid the symptom of disease or symptom or reason or strengthen another kind of therapeutical agent can be contained in term " treatment significant quantity ".
" the treatment significant quantity " of the application's term used refers to be enough to provide treatment benefit in treatment or dispose in disease or symptom or to delay or minimize the amount of one or more compounds of one or more symptoms relevant with described disease or symptom." the treatment significant quantity " of compound means separately or is combined in other therapies the amount treated or dispose and provide the therapeutical agent for the treatment of benefit in described disease or symptom.The amount of the therapeutic efficiency improving overall therapeutic, reduce or avoid the symptom of disease or symptom or reason or strengthen another kind of therapeutical agent can be contained in term " treatment significant quantity ".When being applied to individually dosed indivedual activeconstituents, described term only refers to this composition.When being applied to combination, no matter be combination, continuous or administration simultaneously, described term refers to the combined amount of the activeconstituents producing result for the treatment of.Formula (I) compound and pharmaceutical salts described above.In compatible with other composition of preparation and harmless to its recipient meaning, one or more carriers, thinner or vehicle must be acceptable.According to another aspect of the present invention, additionally provide the preparation method of pharmaceutical preparation, it comprises formula (I) compound or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers, thinner or mixed with excipients.The application's term " pharmaceutical " used refers to that described compound, material, composition and/or formulation are suitable for the contact tissue of patient and without excessive toxicity, stimulation, anaphylaxis or other problem or complication within the scope of rational medical judgment, with rational benefit/risk than conforming to and be effective for the purposes desired by it.
Pharmaceutical preparation can provide containing the unit dosage of predetermined amount activeconstituents by per unit dosage.Dosage level is about 0.01 to about 250 mg/kg (" mg/kg ") body weight/day, and preferably the compounds of this invention of about 0.05 to about 100mg/kg body weight/day is the typical doses in the monotherapy of prevention and therapy disease.Usually, pharmaceutical composition of the present invention by administration every day about 1 to about 5 times, or with the administration of continuous infusion mode.Above-mentioned administration can be used as long-term or short-term therapy.The amount that can combine the activeconstituents to produce single formulation with carrier substance will depend on the severity of treated symptom, symptom, administration time, route of administration, the excretion rate of compound used therefor, the age for the treatment of time length and patient, sex, body weight and healthy state and change.Preferred unit dose formulations is the preparation containing above-mentioned per daily dose or sub-doses or their suitable fractions of active ingredient.The available low dose of begin treatment being substantially less than compound optimal dose.After this, dosage is increased until reach the best effect in this situation with little increment.Usually, compound optimum does not cause any concentration level that is unfavorable or harmful side effect to carry out administration generally to provide effective result.
When the present composition comprises the combination of the compounds of this invention and one or more other therapeutic or preventative medicament, in monotherapy scheme, described compound and other medicament described usually all with about 10% to 150% of usual institute dosage and preferably the dosage level of about 10% to 80% provide.
The compounds of this invention can with one or more other therapeutic or preventative pharmaceutical agent combinations administration.Such as, when being used for the treatment of pain, other possible medicament comprises immunosuppressor, anti-inflammatory agent and/or is used for the treatment of other medicament of pain.
The immunosuppressor being applicable to method and composition of the present invention comprises immunosuppressor as known in the art.Example comprises aminopterin (aminopterin), azathioprine (azathioprine), ciclosporin (cyclosporinA), Beracilline (D-penicillamine), gold salt (goldsalts), Oxychloroquine (hydroxychloroquine), leflunomide (leflunomide), methotrexate (methotrexate), Minocycline HCl (minocycline), rapamycin (rapamycin), sulfasalazine (sulfasalazine), tacrolimus (tacrolimus) (FK506) and their pharmaceutical salts.Concrete immunosuppressor is methotrexate.
Other example of immunosuppressor comprises anti-TNF antibody, such as adalimumab (adalimumab), match trastuzumab (certolizumabpegol), etanercept (etanercept) and infliximab (infliximab).Other immunosuppressor comprises interleukin-1 blockers, such as Kineret (anakinra).Other immunosuppressor comprises anti-B cell (CD20) antibody, such as Rituximab (rituximab).Other immunosuppressor comprises T cell activation blocker, such as Orencia (abatacept).
Other immunosuppressor comprises inosine monophosphate dehydrogenase inhibitor, such as mycophenolate mofetile (mycophenolatemofetil)
with mycophenolic acid (mycophenolicacid)
The anti-inflammatory drugs being applicable to method and composition of the present invention comprises anti-inflammatory drugs as known in the art.Example comprises glucocorticosteroid (glucocorticoid) and NSAID.The example of glucocorticosteroid comprises aldosterone (aldosterone), beclometasone (beclometasone), Betamethasone Valerate (betamethasone), Kendall compound (cortisone), Doca (deoxycorticosterone), dexamethasone (dexamethasone), fluohydrocortisone (fludrocortisones), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisolone), prednisolone (prednisolone), prednisone (prednisone), triamcinolone (triamcinolone) and their pharmaceutical salts.
The example of NSAID comprises salicylic acid salt (such as, acetylsalicylic acid (aspirin), amoxycilline Trihydrate bp (amoxiprin), Benorilate (benorilate), choline salicylate magnesium (cholinemagnesiumsalicylate), diflunisal (diflunisal), Fa Sila amine (faislamine), wintergreen oil (methylsalicylate), magnesium salicylate (magnesiumsalicylate), sasapyrin (salicylsalicylate) and their pharmaceutical salts), aryl alkanoic acid class (such as, diclofenac (diclofenac), Aceclofenac (aceclofenac), acemetacin (acemetacin), Bromfenac (bromfenac), R-ETODOLAC (etodolac), indomethacin (indometacin), nabumetone (nabumetone), sulindac (sulindac), tolmetin (tolmetin) and their pharmaceutical salts), arylprop acids (such as, Ibuprofen BP/EP (ibuprofen), carprofen (carprofen), fenbufen (fenbufen), fenoprofen (fenoprofen), flurbiprofen (flurbiprofen), Ketoprofen (ketoprofen), ketorolac (ketorolac), loxoprofen (loxoprofen), Naproxen Base (naproxen), oxaprozin (oxaprozin), tiaprofenic acid (tiaprofenicacid), sutoprofen (suprofen) and their pharmaceutical salts), aryl-anthranilic acid class (such as, meclofenamic acid (meclofenamicacid), mefenamic acid (mefenamicacid) and their pharmaceutical salts), pyrazolidine derivatives class (such as, Azapropazone (azapropazone), Sulpyrine (metamizole), Tacote (oxyphenbutazone), phenylbutazone (phenylbutazone), sulfinpyrazone (sulfinprazone) and their pharmaceutical salts), former times health class (oxicam) (such as lornoxicam (lornoxicam), meloxicam (meloxicam), piroxicam (piroxicam), tenoxicam (tenoxicam) and their pharmaceutical salts), cox 2 inhibitor class (such as, celecoxib (celecoxib), Etoricoxib (etoricoxib), Prexige (lumiracoxib), parecoxib (parecoxib), rofecoxib (rofecoxib), valdecoxib (valdecoxib) and their pharmaceutical salts) and Sulphonanilide class (sulphonanilides) (such as, nimesulide (nimesulide) and pharmaceutical salts thereof).
Other medicament being used for the treatment of pain (including but not limited to neurogenic pain and inflammatory pain) includes but not limited to following medicament, such as lyrica (pregabalin), lignocaine (lidocaine), duloxetine (duloxetine), gabapentin (gabapentin), Carbamzepine (carbamazepine), capsicine (capsaicin) and other serotonin (serotonin)/norepinephrine (norepinephrine)/Dopamine HCL (dopamine) cell reabsorption inhibitor and opiate (opiate) (such as OxyContin (oxycontin), morphine (morphine) and morphine monomethyl ether (codeine)).
Treating in the pain that caused by known disease or symptom (such as diabetes, infection (such as zoster or HIV) or cancer), the compounds of this invention can with one or more other therapeutic for potential disease or the patient's condition or preventative pharmaceutical agent combinations.Such as, when being used for the treatment of diabetic neuropathy (diabeticneuropathy), the compounds of this invention can with one or more antidiabetics, antihyperglycemic agents, lipid-lowering agent/lipid lowering agent, diet pill, hypotensive agent and appetite-inhibiting agent combination medicine-feeding.The example of antidiabetic comprises biguanides (such as, N1,N1-Dimethylbiguanide (metformin), phenformin (phenformin)), Glucosidase inhibitor class (such as, acarbose (acarbose), miglitol (miglitol)), insulin type (comprising insulin secretagogue element analogue and euglycemic agent), meglitinides (meglitinides) (such as, repaglinide (repaglinide)), sulfonylurea (such as, glimepiride (glimepiride), Glyburide (glyburide), gliclazide (gliclazide), P-607 (chlorpropamide) and Glipizide (glipizide)), biguanides/glyburide combination (such as, lattice Shandong gas (Glucovance)), thiazolidinediones (such as, troglitazone (troglitazone), rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone)), PPAR-alfa agonists, PPAR-gamma agonist, PPAR α/γ dual agonists, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitor, other agonist of glucagon-like peptide-1 (GLP-1) or GLP-1 acceptor, DPP IV (DPP4) inhibitor and white (co-transporter) 2 (SGLT2) inhibitor of sodium glucose co-transporter 2 (such as, Da Gelie clean (dapagliflozin), Ka Gelie clean (canagliflozin) and LX-4211).
Pharmaceutical preparation can be suitable for by any suitable administration, such as by oral (comprise containing clothes or sublingual), per rectum, intranasal, locally (comprise containing clothes, sublingual or through skin), transvaginal or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or intradermal injection or infusion) administration.Above-mentioned preparation is prepared by the known any method of pharmaceutical field (such as making activeconstituents and one or more carriers or excipient composition).Preferred oral administration or pass through drug administration by injection.
The pharmaceutical preparation being suitable for oral administration can be discrete unit form, such as capsule or tablet; Powder agent or granule; Solution in water-based or non-aqueous liquid or suspensoid; Edible foam (foam) or foaming agent (whip); Or oil-in-water liq emulsion or water-in-oil emulsion.
Such as, in order to oral administration in the form of a tablet or capsule, described active medicine component can combine with oral, nontoxic medicinal inert carrier (such as ethanol, glycerine, water etc.).Powder prepares by compound powder being broken to suitable fineness and such as, mixing with the pharmaceutical carrier pulverized similarly (such as edible carbohydrate, starch or N.F,USP MANNITOL).Also can comprise seasonings, sanitas, dispersion agent and tinting material.
Capsule is by preparing powdered mixture as mentioned above and prepared by the gelatin shell of filling molding.Before stuffing operation, glidant and lubricant such as colloid silica, talcum, Magnesium Stearate, calcium stearate or solid polyethylene glycol can be added in powdered mixture.The availability of medicine when also can add disintegrating agent or solubilizing agent such as aga agar, calcium carbonate or sodium carbonate to improve ingestible capsule agent.
In addition, when needing or if desired, also suitable tackiness agent, lubricant, disintegrating agent and tinting material can be mixed in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural gum and synthetical glue (such as gum arabic, tragacanth gum or sodiun alginate), carboxymethyl cellulose, polyoxyethylene glycol etc.Sodium oleate, sodium-chlor etc. is comprised for the lubricant in these formulations.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.Prepare tablet by the following method: such as prepare powdered mixture, granulating or hit pressure, add lubricant and disintegrating agent and be pressed into tablet.Prepare powdered mixture by the following method: the mixture suitably pulverized is mixed with above-mentioned thinner or matrix (base) and optionally with tackiness agent (such as carboxymethyl cellulose, alginate, gelatin or Polyvinylpyrolidone (PVP)), dissolve delayer (such as paraffin), absorb accelerator (such as quaternary ammonium salt) and/or absorption agent (such as wilkinite, kaolin or Si Liaodengji dicalcium phosphate feed grade) again.Make powdered mixture granulating by the following method: soak with tackiness agent (such as the solution of syrup, starch paste, Acadia's rubber cement or Mierocrystalline cellulose or polymeric material) and force it to pass screen cloth.As the alternative method of granulating, powder can be made to pass tabletting machine and result be the incomplete shaping being cracked into particle hit laminate.Can by means of add stearic acid, stearate, talcum or mineral oil come lubricated granules with prevent adhere to and tablet forming dies.Then the mixture through lubrication is pressed into tablet.Also the compounds of this invention and free-pouring inert support can be combined and without granulating or hit and press step to be directly compressed into tablet.Can provide by the coating of the seal coating of shellac, sugar or polymeric material and the coat composed transparent or opaque supercoat of the polishing of wax.Dyestuff can be added to distinguish different unitary doses in described coating.
Oral liquid (such as solution, syrup and elixir) can be prepared by unit dosage, thus make specified rate contain the compound of predetermined amount.Syrup by compound is dissolved in suitable flavoring the aqueous solution in prepare, elixir is then by using nontoxic vehicle to prepare.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ether), sanitas, flavoring additive (such as spearmint oil or natural sweetener or asccharin or other artificial sweetener) etc.
Time suitable, the dosage unit preparations microencapsulation of oral administration can be used for.Described preparation also can such as be prepared by particulate matter is coated with or is embedded in polymkeric substance, wax etc., to extend or sustained release.
The form administration of formula (I) compound and pharmaceutical salts all right liposome delivery system such as small unilamellar vesicle, large unilamellar vesicle and multilamelar liposome.Liposome can be formed by multiple phosphatide such as cholesterol, stearylamine or phosphatidylcholine.
Formula (I) compound and pharmaceutical salts thereof are also by using monoclonal antibody to send as the individual carriers with compound molecule coupling.Described compound also can with as can the soluble polymer coupling of target medicine carrier.Above-mentioned polymkeric substance can comprise the polyethylene-oxide polylysine that Polyvinylpyrolidone (PVP), pyran co-polymer, poly-hydroxypropylmethacrylamide phenol, poly-hydroxyethyl l-asparagine phenol or replacement have palmitoyl residues.In addition, described compound can be applicable to a class biodegradable polymers coupling realizing drug controlled release, the crosslinked or amphipathic nature block polymer of described polymkeric substance such as poly(lactic acid), poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.
The pharmaceutical preparation being suitable for percutaneous dosing can be used as and is intended to keep the discrete patches of close contact long period to provide with the epidermis of recipient.Such as, activeconstituents by such as PharmaceuticalResearch1986,3 (6), in 318, the iontophoresis of large volume description is by patch delivery.
The pharmaceutical preparation being suitable for topical can be formulated as ointment, ointment, suspensoid, lotion, powder agent, solution, paste, gelifying agent, sprays, aerosol or finish.
The pharmaceutical preparation being suitable for per rectum administration can be used as suppository or enema provides.
The pharmaceutical preparation (wherein carrier is solid) being suitable for nose administration comprises the coarse meal that particle diameter is such as 20 to 500 microns, and it, to adopt the mode administration entered from snuffing, namely sucks administration by the container of the accommodation powder pressing close to nose via nasal meatus fast.For comprising the aqueous solution or the oil solution of activeconstituents with the appropriate formulation (wherein carrier is for liquid) of nasal spray agent or nasal drop administration.
Be suitable for comprising particulate pulvis or spray by the pharmaceutical preparation of inhalation, it can produce by means of the pressurised aerosol of various types of dosing, spraying gun or insufflator.
The pharmaceutical preparation being suitable for intravaginal administration can be used as hysterophore, tampon, ointment, gelifying agent, paste, foam or sprays to provide.
The pharmaceutical preparation being suitable for administered parenterally comprises water-based or the non-aqueous sterile injection solution of the solute that the blood that can contain antioxidant, buffer reagent, fungistat and make preparation and intended recipient etc. is opened; With water-based and the non-aqueous sterile suspensions that can comprise suspending agent and thickening material.Preparation unitary dose or multi-dose container (ampoule such as sealed and bottle) form can provide and under can being stored in lyophilize (freeze-drying) condition, only need before facing use, add sterile liquid carrier such as water for injection.Extemporaneous injection solutions and suspension can be prepared by sterilized powder agent, granule and tablet.
Should be understood that, except the above-mentioned composition specifically mentioned, consider the type of described preparation, described preparation also can comprise other medicament common in this area, and the preparation being such as applicable to oral administration can comprise correctives.
Term " patient " comprises the mankind and other Mammals.
Except as otherwise noted, term " disposal ", " process " and " control " are contained the recurrence of disease specific or illness described in patient that pre-tetrandra root suffers from disease or illness and/or are extended the time that the patient having suffered from disease or illness keeps alleviating.Described term contain regulate disease or illness threshold value, development and/or time length, or change the mode that patient responds to disease or illness.
Term " treatment " refers to: (i) can easily suffer from certain disease, illness and/or symptom but not yet be diagnosed as the appearance preventing described disease, illness and/or the patient's condition in the patient suffering from described disease, illness and/or symptom; (ii) suppress disease, illness and/or symptom, that is, make it develop stagnation; (iii) alleviate disease, illness and/or symptom, that is, make described disease, illness and/or symptom disappear.
There is when this invention is intended to contain by synthetic method or prepared by metabolic process (being included in metabolic process or external metabolic process of carrying out that in the mankind or animal body, (in body) carries out) compound of formula (I).
Abbreviation used in the application, comprises the abbreviation in following illustrative approach and embodiment particularly, is well known to a person skilled in the art.Some abbreviations use as follows: HATU is O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate; BOP is benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate; EDC is 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; TBTU is O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate; THF is tetrahydrofuran (THF); DMF is DMF; RT or rt or r.t. is room temperature or retention time (context decision); t
rfor retention time; DCM is methylene dichloride; Dppf is 1,1'-bis-(diphenylphosphino) ferrocene; LDA is lithium diisopropylamine; Ph is phenyl; BOC or Boc is tert-butoxycarbonyl; OAC or OAc is acetic ester/salt; Ac is ethanoyl; AcCN, ACN or MeCN are acetonitrile; MeOH is methyl alcohol; EtOH is ethanol; EtOAc or EtOAC is ethyl acetate; H is hour; Min is minute; TFA is trifluoroacetic acid; BHT is BHT; DBU is 1,8-diazabicyclo 11 carbon-7-alkene; DIEA or DIPEA is diisopropyl ethyl amine; DMSO is dimethyl sulfoxide (DMSO); DCE is 1,2-methylene dichloride; And MeOD is CD
3oD.
Embodiment
Now describe the present invention in conjunction with some embodiment, described embodiment is not intended to limit scope of the present invention.On the contrary, the present invention is contained and can be included in all replacement schemes within right, amendment and equivalents.Therefore, the following example comprising specific embodiments will illustrate one practice of the present invention, should be understood that, described embodiment is for illustration of some embodiment and believes for the most useful and description of easy understand of its program and conceptual aspect presents to provide.
The compounds of this invention can use the reaction described in this part and technology and other synthetic method known to persons of ordinary skill in the art to prepare.Described reaction is being suitable for agents useful for same and material and is being suitable for carrying out in the solvent carrying out transforming.In addition, in the description of following synthetic method, should be understood that, select the standard conditions of all reaction conditionss (comprising selected solvent, temperature of reaction, duration of experiment and finishing sequence) as this reaction of proposition, this should be easy to as those skilled in the art are approved.One skilled in the art will appreciate that the functional group that molecule each several part exists with the reagent proposed and must react compatible.To be apparent to those skilled in the art for the substituent above-mentioned restriction that reaction conditions is compatible and therefore must use alternative method.
Method preparation formula 8 compound summarized by scheme 1, wherein R
1and R
2for H, alkyl, cycloalkyl or thiazolinyl.The suitable phenates propargyl halide of suitable replacement is carried out alkylation in envrionment temperature, obtains the propargyl ether 2 expected.The Wittig of the aldehyde functional group in 2 and suitable Wittig reagent reacts the phenol that can form expectation, and it is the mixture of E, Z mixture, and wherein E-isomer is primary product.By in solvent such as methylene dichloride at dewatering agent such as MgSO
4react with 1,1-dimethylhydrazine under existing, by the α obtained thus, beta-unsaturated aldehyde isomer mixture 3 changes into hydrazone derivative 4.2, under the free-radical scavengers existence of 6-di-tert-butyl-4-methy phenol, in solvent such as sym-trimethylbenzene, the rough hydrazone 4 obtained thus is made to carry out [4+2] cycloaddition reaction (Dolle in molecule, R.E.et.al.TetrahedronLett.1988,29,6349-6352), obtain cyclisation product 5.Use reaction conditions well known to those skilled in the art, react with the amine through protecting in the linked reaction of palladium chtalyst and the bromide in 5 can be replaced.Finally by such as ProtectiveGroupsinOrganicSynthesis (Greene, Wuts; 3
rded., 1999, JohnWiley & Sons, Inc.) described in method blocking group is removed, obtain intermediate 7.Formula 7 compound can with carboxylic acid (R
3c (O) OH) carry out coupling in following condition: use Standard peptide coupling reagents such as HATU, BOP, EDC or TBTU, in alkali such as N, N-diisopropyl ethyl amine and solvent such as THF, 20 DEG C to 80 DEG C temperature, form formula 8 compound.Or formula 7 compound can with acyl chlorides (R
3c (O) Cl) carry out coupling.If R
3containing through the amine groups of protection or other functional group, by with such as ProtectiveGroupsinOrganicSynthesis (Greene, Wuts; 3
rded., 1999, JohnWiley & Sons, Inc.) described in suitable agent treated substrate, obtain formula (I) compound, wherein R
1and R
2=H, alkyl, cycloalkyl or thiazolinyl.
Scheme 1
By method preparation formula 17 or 18 compound, the wherein R of general introduction in scheme 2
1and R
2for H.By with such as ProtectiveGroupsinOrganicSynthesis (Greene, Wuts; 3
rded., 1999, JohnWiley & Sons, Inc.) described in suitable reagent such as (Boc) 2O process substrate, protection aniline 9, obtains 10.At palladium catalyst such as PdCl
2(dppf) and alkali such as potassium acetate or potassiumphosphate exist under, in solvent such as diox, THF or toluene, 20 DEG C to 150 DEG C temperature, the bromide conversion in 10 can be become boric acid ester 11 with two (tetramethyl ethylene ketone conjunction) two boron.Available DMF and alkali such as LDA carries out the conversion of 12, obtains aldehyde 13.Last 12 with boric acid ester 11 at use alkali such as cesium carbonate and the catalyzer such as Pd (PPh such as described in Zhang, Leiet.al. (JournalofMedicinalChemistry, 2011,54,1724 – 1739)
3)
4standard Suzuki (Suzuki) coupling condition under carry out coupling, can 14 be obtained.Original reagent such as sodium borohydride is gone back in use can be reduced into alcohol 15 by aldehyde 14.In solvent such as THF, under an inert atmosphere, the limited core 16 of deprotection can be obtained at 100 DEG C with hydride source such as sodium hydride process alcohol 15.Under using Standard peptide coupling reagents such as HATU, BOP, EDC or TBTU such as THF existing at alkali such as N, N-diisopropyl ethyl amine and solvent, 20 DEG C to 80 DEG C temperature, by compound 16 can with carboxylic acid (R
3c (O) OH) coupling, form formula 17 compound.Or, formula 16 compound can with acyl chlorides (R
3c (O) Cl) carry out coupling, obtain formula 17 compound, or with chloro-formic ester (R
3oC (O) Cl) carry out coupling, obtain formula 18 compound.If R
3containing through the amine groups of protection or other functional group, then by with such as ProtectiveGroupsinOrganicSynthesis (Greene, Wuts; 3
rded., 1999, JohnWiley & Sons, Inc.) described in suitable agent treated substrate removing blocking group, obtain formula (I) compound, wherein R
1and R
2=H.
Scheme 2
By method preparation formula 19 or 20 compound, the wherein R of general introduction in scheme 3
5for halogen.By with halogenating agent such as N-bromosuccinimide process preparation formula 19 or 20 compound.Via the linked reaction of palladium chtalyst, halogen is changed into 21 or 22 further, described reaction comprises reaction conditions well known to those skilled in the art such as suzuki reaction, Shi Dile (Stille) reaction or root bank (Negishi) reaction, obtain formula (I) compound, wherein R
5=CN, alkyl, haloalkyl, aryl or heteroaryl.
Scheme 3
By method preparation formula 32 compound of general introduction in scheme 4, wherein R
4=NHAc is at palladium catalyst such as PdCl
2(dppf) and alkali such as potassium acetate or potassiumphosphate exist under, in solvent such as diox, THF or toluene, 20 DEG C to 150 DEG C temperature, with two (tetramethyl ethylene ketone closes) two boron, iodo-for fluoro-for 2-1-4-oil of mirbane is changed into boric acid ester 23.4-chloropyridine-2-amine and halogenating agent such as N-bromosuccinimide carries out halogenation and can obtain compound 24.Amino with reagent such as Acetyl Chloride 98Min. acidylate, then use standard conditions such as 2,4,6-triethylene basic ring three boroxanes at palladium catalyst such as Pd (PPh
3)
4or Pd (OAc)
2under existing with alkali such as sodium carbonate, cesium carbonate, salt of wormwood or potassiumphosphate, in solvent such as DME, DMF, toluene, the temperature raised, carries out Suzuki coupling, can obtain formula 26 compound.Use reagent such as perosmic anhydride and sodium periodate that vinyl is carried out oxicracking, obtain aldehyde 27.Use as Zhang, Leiet.al. (JournalofMedicinalChemistry, 2011,54,1724 – 1739) described in the condition of employing alkali such as cesium carbonate and catalyzer such as Pd (PPh3) 4 make 27 and 23 to carry out Suzuki coupling, can 28 be obtained.Use reductive agent such as sodium borohydride aldehyde 28 can be reduced into alcohol 29.In solvent such as THF, under an inert atmosphere, the core 30 of cyclisation can be obtained at 100 DEG C with hydride source such as sodium hydride process alcohol 29.Use standard conditions such as to carry out hydrogenation with palladium/carbon, compound 30 is reduced into amine, obtains aniline 31.
Under using Standard peptide coupling reagents such as HATU, BOP, EDC or TBTU such as THF existing at alkali such as N, N-diisopropyl ethyl amine and solvent, 20 DEG C to 80 DEG C temperature, compound 31 can with carboxylic acid (R
3c (O) OH) coupling, form formula 32 compound.Or, formula 31 compound can with acyl chlorides (R
3c (O) Cl) carry out coupling, obtain formula 32 compound.If R
3containing through the amine groups of protection or other functional group, then by with such as ProtectiveGroupsinOrganicSynthesis (Greene, Wuts; 3
rded., 1999, JohnWiley & Sons, Inc.) described in suitable agent treated substrate removing blocking group, obtain formula (I) compound, wherein R
4=NHAc.
Scheme 4
The various analogues of operational version 1-4 synthesis are listed in table 1a and 1b.Functional (the AAK1IC of AAK1 of selected compounds
50) and cellularity (cell IC (nM)
50(nM)) usefulness is with following IC
50scope is listed: a=1-10nM; B=10-100nM; C=100-1205nM.
Table 1a
Table 1b
In the examples below that, Bruker400 or 500MHzNMR spectrograph records proton N MR spectrum.With the δ value report chemical shift relative to tetramethylsilane.Use at least one following method with the ShimadzuLC of WatersMicromassZQ coupling on carry out liquid chromatography (LC)/mass spectrum (MS).The following method of at least one is used to obtain HPLC retention time.
LC-MS method:
Method A:PhenomenexC182x50mm (3 μm), A=95%H
2o/5%MeCN, B=95%MeCN/5%H
2o, Modifier10mMNH
4oAc, 0.00min=0%B, 4min=100%B5min=100%B, flow velocity=0.8mL/min
Method B:PhenomenexC182x50mm (3 μm), A=95%H
2o/5%ACN, B=95%MeCN/5%H
2o, Modifier10mMNH
4oAc, 0.00min=30%B, 4min=100%B5min=100%B, flow velocity=0.8mL/min
LC/MS method C=post: PUROSPHERstarRP-18 (4X55mm), 3 μm; Damping fluid: 20mMNH
4oAC/ water; Mobile phase A: damping fluid+ACN (90+10); Mobile phase B: damping fluid+MeCN (10+90); Flow velocity: 2.5mL/min)
LC/MS method D=post: ZORBAXSBC18 (46X50mm), 5 μm; Holotype mobile phase A: 10%MeOH – 90%H2O – 0.1%TFA; Mobile phase B: 90%MeOH – 10%H
2o – 0.1%TFA; Flow velocity: 5mL/min)
Method E:XbridgeBEHC182x50mm (2.5 μm), A=0.1%HCOOH/H
2o, B=0.07%HCOOH/MeCN, 0.00min=10%B, 1.5min=100%B3min=100%B, flow velocity=1.0mL/min
Method F:AcentisExpressC182x50mm (2.7 μm), damping fluid: 10mMNH
4oAC/ water pH=4.5; Mobile phase A: damping fluid+ACN (98:2); Mobile phase B: damping fluid+MeCN (2:98); Flow velocity: 1.0mL/min)
Method G:Poroshell1203x50mm (2.7 μm), damping fluid: 10mMNH
4oAC/ water, is adjusted to pH=5 with formic acid; Mobile phase A: damping fluid+ACN (90:10); Mobile phase B: damping fluid+MeCN (10:90); Flow velocity: 1.5mL/min)
Chiral HPLC Method:
Method A:CHIRALCELOJH (250x4.6) mm5 micron
Moving phase: 0.2%DEA/ normal hexane: ethanol (80:20)
Embodiment 1
(R)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
The bromo-2-of part A .4-(Propargyl oxygen base) phenyl aldehyde
The solution 1NNaOH aqueous solution of bromo-for 4-Benzaldehyde,2-hydroxy (3.0g, 24.9mmol) in MeOH (150mL) (15.7mL, 1.05 equivalents) is processed.Concentrating under reduced pressure gained yellow solution.EtOH (30mL) to be added in resistates and decompression concentrated solution.Priority EtOH (30mL) and heptane (50mL) repeat above-mentioned steps.Gained yellow powder sodium salt is dissolved in DMF (60mL) and also adds the solution of propargyl bromide in toluene (80wt%, 2.33mL, 1.4 equivalents) wherein by adjoint stirring.Reaction mixture is stirred 22h in envrionment temperature, after this decompression removing volatile matter.Resistates is distributed between EtOAc (70mL) and water (40mL).Organic layer is separated and uses charcoal (~ 1g) to process, then dry (Na
2sO
4) and filter.Concentrating under reduced pressure filtrate.By the crystallization from EtOAc and hexane (3:7) of gained resistates.Product I is the bromo-2-of 4-(Propargyl oxygen base) phenyl aldehyde (893mg), and it is colorless needles.Concentrating under reduced pressure mother liquor is also carrying out crystallization from EtOAc and hexane (7:93), obtains another crowd of bromo-2-of product II4-(Propargyl oxygen base) phenyl aldehyde (1.9g).Mother liquor carried out concentrated again and carry out crystallization again as aforementioned.Product III, obtains another crowd of bromo-2-of 4-(Propargyl oxygen base) phenyl aldehyde (344mg).Merged by whole three batches of products, obtain amounting to 3.14g (87% productive rate) 4-bromo-2-(Propargyl oxygen base) phenyl aldehyde, it is colorless needles.
1hNMR (500MHz, CDCl
3) δ ppm10.43 (s, 1H), 7.74 (d, J=8.2Hz, 1H), 7.31 (d, J=1.5Hz, 1H), 7.24-7.28 (m, 1H), 4.85 (d, J=2.4Hz, 2H), 2.64 (t, J=2.4Hz, 1H); LCMS (ESI) m/e239.0,241.0Br pattern [(M+H)
+, C
10h
8brO
2calculated value 239.0].
Part B. (E)-3-(the bromo-2-of 4-(Propargyl oxygen base) phenyl) propenal
The bromo-2-of 4-(the Propargyl oxygen base) phenyl aldehyde (0.852g in THF (20mL) will be suspended in; 3.56mmol) with formyl radical methylene triphenyl phosphine (phosphorane) (2.2g; 7.12mmol; 2 equivalents) mixture stir 18h in envrionment temperature, then stir 24h again at 50 DEG C.By reaction mixture by using EtOAc: the silica gel bed (~ 25g) of hexane (1:4,300mL) wash-out filters.Concentrating under reduced pressure filtrate and by resistates by use EtOAc: the silica gel chromatography of the linear gradient of hexane (1:19 to 1:9) carries out purifying.Containing title compound and Z-isomer thereof, (ratio is 39:11 to concentrating under reduced pressure, identified by NMR) the fraction of merging, obtain (E)-3-(the bromo-2-of 4-(Propargyl oxygen base) phenyl) propenal (0.69g, 57% productive rate).
1HNMR(500MHz,CDCl
3)δ9.71(d,J＝7.6Hz,1H),7.77(d,J＝16.2Hz,1H),7.45(d,J＝8.2Hz,1H),7.26-7.17(m,2H),6.77(dd,J＝16.2,7.6Hz,1H),4.82(d,J＝2.4Hz,1H),4.80-4.75(m,1H),2.62(t,J＝2.4Hz,1H)。Z-isomer shows aldehyde proton at δ 9.87 (d, J=7.9Hz) and shows the less cis-coupling (J=11.4Hz) of phenol proton at δ 6.22; LCMS (ESI) m/e265.0,267.0Br pattern [(M+H)
+, C
12h
10brO
2calculated value 265.0].
C part. (E)-2-((E)-3-(the bromo-2-of 4-(Propargyl oxygen base) phenyl) acrol)-1,1-dimethylhydrazine
Will containing anhydrous MgSO
4(16g) (E)-3-(the bromo-2-of 4-(the Propargyl oxygen base) phenyl) solution of propenal (2.85g, 10.8mmol) in methylene dichloride (200mL) cools with being stirred in ice bath.In ice-cooled solution, drip 1,1-dimethylhydrazine (2.45mL, 32.4mmol), then reaction mixture be warmed to envrionment temperature and stir 18h.Concentrating under reduced pressure volatile matter and by resistates in succession with methylene dichloride (50mL), ethylene dichloride (50mL) and heptane (50mL) coevaporation.Obtain (E)-2-((E)-3-(the bromo-2-of 4-(Propargyl oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (2.7g, 90% productive rate, 90% purity), it is yellow powder.
1hNMR (500MHz, CDCl
3) δ 7.39 (d, J=7.9Hz, 1H), 7.20-7.10 (m, 3H), 7.00-6.86 (m, 2H), 4.75 (d, J=2.3Hz, 2H), 2.95 (s, 6H), 2.58 (t, J=2.3Hz, 1H); LCMS (ESI) m/e307.0,309.0Br pattern [(M+H)
+, C
14h
16brN
2o calculated value 307.0].
The bromo-5H-chromene of D part .8-also [3,4-c] pyridine
By (E)-2-((E)-3-(the bromo-2-of 4-(Propargyl oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (116mg, 374mmol) He 2,6-di-tert-butyl-4-methy phenol (82mg, solution 374mmol) in sym-trimethylbenzene (4.5mL) carries out degassed about 15min at 50 DEG C by bubbling argon, carries out supersound process in heavy sheet glass bottle simultaneously.Under argon gas bottle is covered, with being heated with stirring to 140 DEG C and keeping 138h in oil bath.By reaction mixture cooling environment temperature and concentrating under reduced pressure solvent.Using dark residue by with EtOAc: methylene dichloride (1:19) carries out purifying as the silica gel chromatography of eluent.Merge the fraction containing expectation product and concentrating under reduced pressure, obtain the bromo-5H-chromene of 8-also [3,4-c] pyridine (27mg is 25% productive rate based on 89% purity), it is pale yellow powder.
1hNMR (500MHz, CDCl
3) δ 8.63 (d, J=5.2Hz, 1H), 8.45 (s, 1H), 7.62 (d, J=8.2Hz, 1H), 7.52 (d, J=5.2Hz, 1H), 7.27-7.22 (m, 2H), 5.20 (s, 2H); LCMS (ESI) m/e262.0,264.0Br pattern [(M+H)
+, C
12h
9brNO calculated value 262.0].
E part .5H-chromene is [3,4-c] pyridine-8-carbamate also
By bromo-for 8-5H-chromene also [3,4-c] pyridine (2.5g, 9.54mmol), t-butyl carbamate (6.25g, 53.3mmol), Cs
2cO
3(16.5g, 50.7mmol), XANTPHOS (1.27g, 2.194mmol) and acid chloride (II) (1.33g, 5.91mmol) the solution degas with nitrogen 5min in Isosorbide-5-Nitrae-diox (20mL).By the seal of tube, be heated to 90 DEG C and keep 12h.By mixture via diatomite
filter and concentrating under reduced pressure filtrate.Add water and use ethyl acetate (3x20mL) extracted residues.By organism salt solution (1x20mL) washing merged, with dried over sodium sulfate, filter and concentrating under reduced pressure.Resistates is carried out purifying by preparative TLC (40% ethyl acetate/petroleum ether), obtains 5H-chromene also [3,4-c] pyridine-8-carbamate (2.0g, 6.70mmol, 70% productive rate); LCMS (ESI) m/e299.2 [(M+H)
+, C
17h
19n
2o
3calculated value 299.1].
F part .5H-chromene is [3,4-c] pyridine-8-amine also
By 5H-chromene also [3,4-c] pyridine-8-carbamate (0.157g, 0.526mmol) solution in TFA (2mL, 26.0mmol) at stirring at room temperature 2h.Decompression removing TFA.Resistates used carefully saturated sodium bicarbonate solution (10mL) cancellation and extract with DCM (3x10mL).The organism merged is washed with salt solution (1x10mL), with dried over sodium sulfate, filter, then concentrating under reduced pressure, obtains 5H-chromene also [3,4-c] pyridine-8-amine (0.03g, 0.151mmol, 29% thick productive rate), it is yellow solid, is not further purified namely in next step.LCMS (ESI) m/e199.2 [(M+H)
+, C
12h
11n
2o calculated value 199.1].
G part. (R)-(1-((5H-chromene is [3,4-c] pyridine-8-base also) is amino)-4-methyl isophthalic acid-oxo penta-2-base) t-butyl carbamate
At-10 DEG C to 5H-chromene also [3,4-c] pyridine-8-amine (0.35g, 1.77mmol) and (R)-2-((tert-butoxycarbonyl) amino)-4-methylvaleric acid (0.408g, 1.77mmol) in pyridine (10mL), in stirred solution, drip POCl
3reaction mixture is also stirred 30min in this temperature by (0.21mL, 2.30mmol).By mixture concentrating under reduced pressure, dilute with water (15mL) and use ethyl acetate (3x15mL) to extract.By organism salt solution (1x10mL) washing merged, with dried over sodium sulfate, filter, then concentrating under reduced pressure.By the preparative TLC purifying of resistates by use 50% ethyl acetate/hexane, obtain (R)-(1-((5H-chromene also [3,4-c] pyridine-8-base) amino)-4-methyl isophthalic acid-oxo penta-2-base) t-butyl carbamate (0.5g, 1.22mmol, 69% productive rate).LCMS (ESI) m/e412.2 [(M+H)
+, C
23h
30n
3o
4calculated value 412.2].
H part. (R)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
By (R)-(1-((5H-chromene also [3,4-c] pyridine-8-base) amino)-4-methyl isophthalic acid-oxo penta-2-base) t-butyl carbamate (300mg, solution 0.729mmol) in TFA (562 μ l, 7.29mmol) is at stirring at room temperature 10h.Decompression concentrated solution also passes through preparation HPLC Purification, obtain (R)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide (28mg, 0.09mmol, 12% productive rate), it is yellow solid.
1hNMR (500MHz, methyl alcohol-d
4) δ 8.66 (d, J=6.1Hz, 1H), 8.62 (s, 1H), 8.18 (d, J=6.1Hz, 1H), 8.05 (d, J=8.9Hz, 1H), 7.59 (d, J=2.1Hz, 1H), 7.41 (dd, J=8.5,2.1Hz, 1H), 5.35 (s, 2H), 4.07 (t, J=7.2Hz, 1H), 1.88-1.71 (m, 3H), 1.06 (d, J=0.9Hz, 3H), 1.05 (d, J=0.9Hz, 3H); LCMS (ESI) m/e312.2 [(M+H)
+, C
18h
22n
3o
2calculated value 312.2].
Embodiment 2
(S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
Follow the scheme identical with described in embodiment 1, (S)-2-((tert-butoxycarbonyl) is amino)-4-methylvaleric acid is used in G part, prepare title compound, obtain (S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide.
1hNMR (500MHz, methyl alcohol-d
4) δ 8.69 (d, J=6.1Hz, 1H), 8.65 (s, 1H), 8.24 (d, J=6.4Hz, 1H), 8.07 (d, J=8.9Hz, 1H), 7.62 (d, J=2.1Hz, 1H), 7.43 (dd, J=8.7,2.0Hz, 1H), 5.37 (s, 2H), 4.09 (t, J=7.2Hz, 1H), 1.88-1.73 (m, 3H), 1.08-1.06 (m, 1H), 1.06-1.05 (m, 1H), 1.07 (s, 3H), 1.06 (s, 3H); LCMS (ESI) m/e312.2 [(M+H)
+, C
18h
22n
3o
2calculated value 312.2].
Embodiment 3 and 4
(S)-2-amino-4-methyl-N-((R)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide and (S)-2-amino-4-methyl-N-((S)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide
The bromo-2-of part A .4-(fourth-3-alkynes-2-base oxygen base) phenyl aldehyde
K is added in the solution of the bromo-Benzaldehyde,2-hydroxy (3.0g, 14.92mmol) of 4-in DMF (60mL)
2cO
3(2.063g, 14.92mmol).Reaction mixture is cooled to 0 DEG C, then lasts 10min and drip 3-bromine fourth-1-alkynes (2.98g, 22.39mmol).Mixture be warmed to room temperature (RT) and stir 16h.By in reaction mixture impouring 200mL icy water.Via collecting by filtration gained solid go forward side by side sector-style do.The bromo-2-of gained 4-(fourth-3-alkynes-2-base oxygen base) phenyl aldehyde (3.0g, 11.02mmol, 74% productive rate), it is brown oil.
1hNMR (400MHz, CDCl
3) δ 10.41 (s, 1H), 7.71 (d, J=8.4Hz, 1H), 7.36 (d, J=1.6Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 4.95 (dq, J=2.0Hz, J=2.0Hz, 1H), (2.62 d, J=2.0Hz, 1H); (1.74 d, J=2.0Hz, 3H); LCMS (ESI) m/e253.0,255.0Br pattern [(M+H)
+, C
11h
10brO
2calculated value 253.0].
Part B .3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) propenal
To the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl aldehyde (3.0g, 2-(triphenylphosphanylidene) acetaldehyde (4.69g, 15.40mmol) is added in solution 11.85mmol) in tetrahydrofuran (THF) (60mL).Reaction mixture is heated at 50 DEG C and keeps 90h.Reaction mixture be cooled to room temperature and use salt solution (100mL) cancellation.With ethyl acetate (3x100mL) extraction solution.By the organism of merging with Na
2sO
4drying, filters, then concentrating under reduced pressure.Crude product is carried out purifying by silica gel chromatography (sherwood oil: ethyl acetate), obtain 3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) propenal (1.3g, 4.19mmol, 35% productive rate), it is yellow solid.LCMS (ESI) m/e279.0,281.0Br pattern [(M+H)+, C
13h
12brO
2calculated value 279.0].
C part .2-(3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) acrol)-1,1-dimethylhydrazine
Monohydrate acid magnesium (7.8g, 56.4mmol) is added in 3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) solution of propenal (1.3g, 4.66mmol) in (52mL).Reaction mixture is cooled to 0 DEG C, then lasts 5min and drip 1,1-dimethylhydrazine (1.08mL, 13.97mmol).Then reaction mixture be warmed to room temperature and stir 16h.Reaction mixture is filtered through magnesium sulfate bed, wash with methylene dichloride (100mL), then concentrating under reduced pressure, obtain 2-(3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (1.6g, 4.63mmol, 99% thick productive rate).Material is proceeded, is not further purified.LCMS (ESI) m/e321.0,323.0Br pattern [(M+H)+, C
15h
18brN
2o calculated value 321.1].
The bromo-5-methyl of D part .8--5H-chromene also [3,4-c] pyridine
To 3-(the bromo-2-of 4-(fourth-3-alkynes-2-base oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (1.9g, 5.92mmol) at sym-trimethylbenzene (120mL, BHT (0.026g, 0.118mmol) is added in solution 9.72mmol).By carrying out supersound process under a nitrogen by degassed for solution 15min, then at 140 DEG C of heating 96h.Solution is cooled to room temperature and decompression removing sym-trimethylbenzene.The crude product obtained thus is carried out purifying by using the silica gel chromatography that linear gradient is 5-30% ethyl acetate/hexane, obtain the bromo-5-methyl of 8--5H-chromene also [3,4-c] pyridine (1.1g, 3.98mmol, go through two step 67% productive rates), it is brown oil.LCMS (ESI) m/e276.0,278.0Br pattern [(M+H)+, C
13h
11brNO calculated value 276.0].
E part. (5-methyl-5H-chromene is [3,4-c] pyridine-8-base also) t-butyl carbamate
The bromo-5-methyl of 8--5H-chromene also [3 is successively added in 15mL penstock, 4-c] pyridine (275mg, 0.996mmol) 1, solution in 4-diox (6mL), t-butyl carbamate (652mg, 5.57mmol) with Cs2CO3 (1726mg, 5.30mmol).Reaction mixture is used degas with nitrogen 10min.Add XANTPHOS (133mg, 0.229mmol) and acid chloride (II) (139mg, 0.617mmol).Reaction mass is degassed 10min again.By reaction mixture at 80 DEG C of heating 12h.Mixture is cooled to room temperature, through diatomite
filter, then wash by ethyl acetate.Concentrating under reduced pressure filtrate.Crude product is carried out purifying via silica gel chromatography (sherwood oil: ethyl acetate), obtains (5-methyl-5H-chromene is [3,4-c] pyridine-8-base also) t-butyl carbamate (250mg, 0.71mmol, 72% productive rate).LCMS (ESI) m/e313.2 [(M+H)+, C
18h
21n
2o
3calculated value 313.2].
F part .5-methyl-5H-chromene also [3,4-c] pyridine-8-amine
To (5-methyl-5H-the chromene also [3 being cooled to 0 DEG C, 4-c] pyridine-8-base) t-butyl carbamate (250mg, 4NHCl/ diox (5mL, 20.00mmol) is added in solution 0.800mmol) in methylene dichloride (5mL).Reaction soln is stirred 5min, then at stirring at room temperature 2h at 0 DEG C.Removal of solvent under reduced pressure.Solid with ethyl acetate is washed, obtains 5-methyl-5H-chromene also [3,4-c] pyridine-8-amine hydrochlorate (185mg, 0.744mmol, 93% productive rate).LCMS (ESI) m/e213.0 [(M+H)+, C
13h
13n
2o calculated value 213.1].
G part. ((2S)-4-methyl isophthalic acid-((5-methyl-5H-chromene is [3,4-c] pyridine-8-base also) is amino)-1-oxo penta-2-base) t-butyl carbamate
To 5-methyl-5H-chromene also [3,4-c] pyridine-8-amine hydrochlorate (250mg, ((S)-2-((tert-butoxycarbonyl) is amino)-4-methylvaleric acid (327mg, 1.413mmol) is added in solution 1.178mmol) in pyridine (4mL).Reaction mixture is cooled to-15 DEG C, then drips POCl
3(0.165mL, 1.767mmol).Reaction mixture is stirred 30min, then at stirring at room temperature 1h at-15 DEG C.Decompression removing pyridine.In resistates, add 25mL water and use ethyl acetate (x25mL) extraction solution.The organic layer merged is washed with 1.5NHCl (1x25mL).By organism with Na
2sO
4drying, filters and concentrating under reduced pressure.Thick material is carried out purifying by preparative TLC (80% ethyl acetate/hexane), obtain ((2S)-4-methyl isophthalic acid-((5-methyl-5H-chromene also [3,4-c] pyridine-8-base) amino)-1-oxo penta-2-base) t-butyl carbamate (80mg, 0.19mmol, 16% productive rate).
1hNMR (500MHz, methyl alcohol-d
4) δ 8.49 (d, J=4.8Hz, 1H), 8.40 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.74 (d, J=5.2Hz, 1H), 7.43 (dd, J=2.0Hz, J=2.0Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 5.41 (d, J=6.8Hz, 1H), 4.24 (s, 1H), 1.77-1.68 (m, 1H), 1.64-1.47 (m, 5H), 1.47 (s, 9H), 1.11 (d, J=3.2Hz, 3H) .0.99 (d, J=3.2Hz, 3H); LCMS (ESI) m/e426.2 [(M+H)+, C
24h
32n
3o
4calculated value 426.2].
H part. (S)-2-amino-4-methyl-N-((R)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide and (S)-2-amino-4-methyl-N-((S)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide
Last 2min to ((2S)-4-methyl isophthalic acid-((5-methyl-5H-chromene also [3 being cooled to 0 DEG C, 4-c] pyridine-8-base) amino)-1-oxo penta-2-base) t-butyl carbamate (80mg, 4NHCl/ diox (2mL, 8.00mmol) is slowly added in solution 0.188mmol) in methylene dichloride (2mL).By reaction mixture 0 DEG C of stirring, be then warmed to room temperature and stir 2h.Removal of solvent under reduced pressure.By crude product recrystallization from methanol/ethyl acetate, obtain the mixture of diastereomer.Via chiral preparative HPLC (method A) separating mixture, obtain diastereomer 1 (15mg, 0.04mmol, 21% productive rate) and diastereomer 2 (13mg, 0.03mmol, 21% productive rate).Do not determine the absolute stereochemical on methyl: diastereomer 1 (diastereomer of first wash-out):
1hNMR (400MHz, methyl alcohol-d
4) δ 8.49 (d, J=5.2Hz, 1H), 8.38 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.72 (d, J=5.2Hz, 1H), 7.46 (d, J=2.0Hz, 1H), 7.30 (dd, J=8.4Hz, J=2.0Hz, 1H), 5.41 (q, J=6.8Hz, 1H), 3.59-3.55 (m, 1H), 1.81-1.77 (m, 1H), 1.70-1.66 (m, 5H), 1.02 (d, J=4.4Hz, 3H) .1.0 (d, J=4.4Hz, 3H); LCMS (ESI) m/e326.2 [(M+H)+, C
19h
24n
3o
2calculated value 326.2]; Diastereomer 2 (diastereomer of second wash-out):
1hNMR (400MHz, methyl alcohol-d
4) δ 8.49 (d, J=5.2Hz, 1H), 8.39 (s, 1H), 7.86 (d, J=8.4Hz, 1H), 7.72 (d, J=5.2Hz, 1H), 7.46 (d, J=2.0Hz, 1H), 7.30 (dd, J=8.4Hz, J=2.0Hz, 1H), 5.41 (q, J=6.8Hz, 1H), 3.59-3.55 (m, 1H), 1.81-1.77 (m, 1H), 1.70-1.66 (m, 5H), 1.02 (d, J=4.4Hz, 3H) .1.0 (d, J=4.4Hz, 3H); LCMS (ESI) m/e326.2 [(M+H)+, C
19h
24n
3o
2calculated value 326.2].
Embodiment 5
(2R)-2-amino-4-methyl-N-(5-methyl-5H-chromene is [3,4-c] pyridine-8-base also) valeramide
Follow the scheme identical with described in 4 with embodiment 3, (R)-2-((tert-butoxycarbonyl) is amino)-4-methylvaleric acid is used in G part, prepare title compound, obtain (2R)-2-amino-4-methyl-N-(5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide, it is the 1:1 mixture of diastereomer.
1hNMR (500MHz, methyl alcohol-d
4) δ 8.69 (d, J=6.4Hz, 1H), 8.66 (s, 1H), 8.28 (d, J=6.1Hz, 1H), 8.05 (d, J=8.5Hz, 1H), 7.60 (dd, J=4.4,2.0Hz, 1H), 7.39 (ddd, J=8.7,5.0,2.1Hz, 1H), 5.60-5.50 (m, 1H), 4.11 (t, J=7.2Hz, 1H), 1.86-1.75 (m, 3H), 1.74 (d, J=3.1Hz, 1.5H
diastereomer 1 methyl), 1.72 (d, J=3.4Hz, 1.5H
diastereomer 2 first base), 1.05 (d, J=6.4Hz, 6H); LCMS (ESI) m/e326.2 [(M+H)+, calculated value C
19h
24n
3o
2326.2].
Embodiment 6 and 7
(R)-2-amino-4-methyl-N-((R)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide and (R)-2-amino-4-methyl-N-((S)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide
Be separated the mixture from the diastereomer of embodiment 5 by chirality HPLC (method A), obtain diastereomer 1 (11mg, 0.020mmol) and diastereomer 2 (12mg, 0.024mmol).Do not determine the absolute stereochemical on methyl: diastereomer 1 (diastereomer of first wash-out):
1hNMR (500MHz, methyl alcohol-d
4) δ 8.69 (d, J=6.1Hz, 1H), 8.66 (s, 1H), 8.27 (d, J=6.1Hz, 1H), 8.07 (d, J=8.9Hz, 1H), 7.61 (d, J=2.1Hz, 1H), 7.41 (dd, J=8.7,2.0Hz, 1H), 4.08 (t, J=7.2Hz, 1H), 1.85-1.76 (m, 3H), 1.74 (d, J=6.7Hz, 3H), 1.06 (d, J=1.2Hz, 3H), 1.05 (d, J=1.2Hz, 3H); LCMS (ESI) m/e326.2 [(M+H)+, C
19h
24n
3o
2calculated value 326.2]; Diastereomer 2 (diastereomer of second wash-out):
1hNMR (500MHz, methyl alcohol-d
4) δ 8.69 (d, J=6.1Hz, 1H), 8.66 (s, 1H), 8.27 (d, J=6.1Hz, 1H), 8.07 (d, J=8.9Hz, 1H), 7.62 (d, J=2.1Hz, 1H), 7.41 (dd, J=8.5,2.1Hz, 1H), 5.57 (q, J=6.6Hz, 1H), 4.08 (t, J=7.2Hz, 1H), 1.86-1.77 (m, 3H), 1.74 (d, J=6.7Hz, 3H), 1.06 (d, J=0.9Hz, 3H), 1.05 (d, J=0.9Hz, 3H); LCMS (ESI) m/e326.2 [(M+H)+, C
19h
24n
3o
2calculated value 326.2].
Embodiment 8
(R)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
The bromo-2-of part A .4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl aldehyde
To bromine phenolic aldehyde (2.0g, 10.0mmol) with Copper dichloride dihydrate (43.0mg, DBU (1.78mL, 11.9mmol) is added and by blue-green solution at salt-ice-stirred in water bath 10min in solution 0.32mmol) in acetonitrile (33.1mL).Last 5min and from syringe, drip 3-chloro-3-methyl-Ding-1-alkynes (1.13mL, 10.0mmol) and by reaction mixture at salt-ice-stirred in water bath 3.5h.Removal of solvent under reduced pressure.Resistates is absorbed in EtOAc (350mL) and also uses 1MHCl (33mL) and water (150mL) and salt solution (120mL) to wash.By organic layer drying (Na
2sO4), filter, then concentrating under reduced pressure.Resistates is carried out purifying by silica gel chromatography (10%DCM/ hexane), obtain the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl aldehyde (1.82g, 6.48mmol, 65% productive rate), it is light yellow oil.
1hNMR (500MHz, chloroform-d) δ 10.38 (d, J=0.6Hz, 1H), 7.83-7.62 (m, 2H), 7.33-7.29 (m, 1H), 2.71 (s, 1H), 1.77 (s, 6H) LCMS (ESI) m/e267.0,269.0Br pattern [(M+H)
+, C
12h
12brO
2calculated value 267.0].
Part B .3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) propenal
To the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl aldehyde (1.82g, 2-(triphenylphosphanylidene) acetaldehyde (2.56g, 8.4mmol) is added in solution 6.45mmol) in tetrahydrofuran (THF) (35mL).By reaction mixture at 50 DEG C of heating 90h.Reaction mixture be cooled to room temperature and use salt solution (100mL) cancellation.With ethyl acetate (3x100mL) extraction solution.By the organism of merging with Na
2sO
4drying, filters, then concentrating under reduced pressure.Crude product is carried out purifying via silica gel chromatography (sherwood oil: ethyl acetate), obtain 3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) propenal (1.34g, 3.88mmol, 60% productive rate), it is yellow oil.
1hNMR (500MHz, chloroform-d) δ 9.71 (d, J=7.6Hz, 1H), 7.81 (d, J=1.8Hz, 1H), 7.76 (d, J=16.2Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 7.24 (dd, J=8.9,1.8Hz, 1H), 6.73 (dd, J=16.2,7.9Hz, 1H), 2.71 (s, 1H), 1.77 (s, 6H); LCMS (ESI) m/e293.0,295.0Br pattern [(M+H)+, C
13h
12brO
2calculated value 293.0].
C part .2-(3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) acrol)-1,1-dimethylhydrazine
To 3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) propenal (1.13g, monohydrate acid magnesium (6.5g, 47.0mmol) is added in solution 3.85mmol) in DCM (72mL).Reaction mixture is cooled to 0 DEG C, then lasts 5min and drip 1,1-dimethylhydrazine (0.97mL, 12.78mmol).Then reaction mixture be warmed to room temperature and stir 16h.Reaction mixture is filtered via magnesium sulfate bed, wash with methylene dichloride (100mL), then concentrating under reduced pressure, obtain 2-(3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (1.29g, 3.85mmol, 99% thick productive rate), it is orange solid, is not further purified and can carries out downwards.LCMS (ESI) m/e335.1.0,337.1Br pattern [(M+H)+, C
16h
20brN
2o calculated value 335.1.1].
Bromo-5, the 5-dimethyl-5H-chromenes of D part .8-also [3,4-c] pyridine
To 2-(3-(the bromo-2-of 4-((2-methyl fourth-3-alkynes-2-base) oxygen base) phenyl) acrol)-1,1-dimethylhydrazine (1.13g, BHT (0.74g, 3.37mmol) is added in solution 3.37mmol) in sym-trimethylbenzene (40mL).By solution under a nitrogen by the degassed 15min of supersound process and at 140 DEG C of heating 96h.Solution is cooled to room temperature and decompression removing sym-trimethylbenzene.The crude product obtained thus is carried out purifying by silica gel chromatography (ethyl acetate/hexane), obtains bromo-5, the 5-dimethyl-5H-chromenes of 8-also [3,4-c] pyridine (0.109g, 0.38mmol, goes through two step 11% productive rates), it is brown oil.LCMS (ESI) m/e290.0,292.0Br pattern [(M+H)+, C
14h
13brNO calculated value 290.0].
E part .5,5-dimethyl-5H-chromene also [3,4-c] pyridine-8-amine
Successively 8-bromo-5 is added in penstock, 5-dimethyl-5H-chromene also [3,4-c] pyridine (109mg, 0.334mmol) 1, solution in 4-diox (6mL), t-butyl carbamate (219mg, 1.87mmol) and Cs
2cO
3(579mg, 1.78mmol).Reaction mixture is used degas with nitrogen 10min.Add XANTPHOS (44.5mg, 0.077mmol) and acid chloride (II) (46.5mg, 0.207mmol).By reaction mass degassed 10min again.By reaction mixture at 80 DEG C of heating 12h.Mixture is cooled to room temperature, through diatomite
filter, then wash by ethyl acetate.Concentrating under reduced pressure filtrate.Crude product is carried out purifying via silica gel chromatography (sherwood oil: ethyl acetate), obtain 5,5-dimethyl-5H-chromene also [3,4-c] pyridine-8-amine (7.5mg, 0.033mmol, 10% productive rate) and (5,5-dimethyl-5H-chromene also [3,4-c] pyridine-8-base) t-butyl carbamate (35.6mg, 0.109mmol, 33% productive rate).LCMS (ESI) m/e227.1 [(M+H)
+, C
14h
15n
2o calculated value 227.1] and LCMS (ESI) m/e327.2 [(M+H)
+, C
19h
23n
2o
3calculated value 327.2].
F part. (R)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
The suspension of Fmoc-D-leucine (177mg, 0.5mmol) in methylene dichloride (2mL) is carried out processing and stirring 2h with oxalyl chloride (0.263mL, 3mmol) and 2 DMF.Decompression removing volatile matter.Add ethylene dichloride (20mL) and heptane (30mL) and concentrating under reduced pressure mixture.Repeat twice again, the oxalyl chloride that removing is remaining.Resistates is absorbed in acetonitrile (0.67mL).In second flask, add DIEA (23 μ L, 0.133mmol) and 5,5-dimethyl-5H-chromene also [3,4-c] pyridine-8-amine (15mg, 0.066mmol), then add the solution of acid chloride of aforementioned preparation.By reaction mixture at stirring at room temperature 1h.LC/MS shows initial substance and transforms completely.Concentrating under reduced pressure reaction mixture, is then dissolved in acetonitrile (5mL) again.Add DIEA (500 μ L, 2.86mmol) wherein and carry out Fmoc deprotection.Mixture is at stirring at room temperature 2h.Solution with water (5mL) is diluted and uses EtOAc (3x10mL) to extract.Merge organic layer, with salt solution (1x10mL) washing, dry (Na2SO4), filters, then concentrates under elevated pressure.Resistates is carried out purifying by silica gel chromatography (10%MeOH/DCM), obtain (R)-2-amino-N-(5,5-dimethyl-5H-chromene also [3,4-c] pyridine-8-base)-4-methylpentanamide (20.2mg, 0.043mmol, 65% productive rate).
1hNMR (500MHz, methyl alcohol-d
4) δ 8.73 (s, 1H), 8.69 (d, J=6.4Hz, 1H), 8.32 (d, J=6.4Hz, 1H), 8.09 (d, J=8.9Hz, 1H), 7.60 (d, J=2.1Hz, 1H), 7.41 (dd, J=8.7,2.0Hz, 1H), 4.10 (t, J=7.2Hz, 1H), 1.87-1.81 (m, 3H), 1.79 (d, J=1.8Hz, 6H), 1.07 (s, 3H), 1.06 (s, 3H); LCMS (ESI) m/e340.1 [(M+H)
+, C
20h
26n
3o
2calculated value 340.2]; Specific rotation: [α]
20 d(MeOH)=-34.71 °.
Embodiment 9
(S)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
Follow the scheme identical with described in embodiment 8, in F part, use Fmoc-L-leucine, prepare title compound, obtain (S)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide.
1hNMR (500MHz, methyl alcohol-d
4) δ 8.70 (s, 1H), 8.67 (d, J=6.1Hz, 1H), 8.25 (d, J=6.4Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 7.58 (d, J=2.1Hz, 1H), 7.39 (dd, J=8.9,2.1Hz, 1H), 4.07 (t, J=7.2Hz, 1H), 1.87-1.79 (m, 3H), 1.78 (d, J=1.5Hz, 6H), 1.07 (d, J=1.5Hz, 3H), 1.06 (d, J=1.8Hz, 3H); LCMS (ESI) m/e340.1 [(M+H)
+, C
20h
26n
3o
2calculated value 340.2]; Specific rotation: [α]
20 d(MeOH)=+ 28.51 °.
Embodiment 10
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-sec.-propyl piperidines-2-methane amide
Follow the scheme identical with described in embodiment 1,1-(tert-butoxycarbonyl)-3-sec.-propyl piperidines-2-formic acid is used in G part, prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-sec.-propyl piperidines-2-methane amide.
1hNMR (400MHz, methyl alcohol-d
4) δ 8.65 (d, J=6.0Hz, 1H), 8.60 (s, 1H), 8.12 (d, J=6.0Hz, 1H), 8.04 (d, J=5.2Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 7.40 (d, J=2.0Hz, 1H), 7.37 (d, J=2.0Hz, 1H), 5.34 (s, 2H), 3.62 – 3.58 (m, 1H), 3.18 – 3.15 (m, 1H), 2.18 – 2.08 (m, 2H), 1.98 – 1.91 (m, 2H), 1.90 – 1.79 (m, 2H), 1.05 (s, 3H), 1.04 (s, 3H); LCMS (ESI) m/e352.2 [(M+H)
+, C
21h
26n
3o
2calculated value 352.2].
Embodiment 11
(S)-2-amino-4-methyl-N-(5-oxo-5H-chromene is [3,4-c] pyridine-8-base also) valeramide
Part A .2-(2-methoxyl group-4-nitrophenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane
In room temperature under argon gas, to the bromo-2-methoxyl group of 1--4-oil of mirbane (20g, suspension 86mmol) in DMSO (100mL) adds two (tetramethyl ethylene ketone conjunction) two boron (32.8g, 129mmol) and potassium acetates (25.4g, 259mmol).Reaction mixture is used degas with nitrogen 10min.Add 1,1'-bis-(diphenylphosphino) ferrocene palladium chloride (II) (3.55g, 4.31mmol) and reaction mixture is heated 12h at 90 DEG C.By reaction mixture through diatomite
filter.Filtrate water (100mL) is diluted and uses ethyl acetate (3x500mL) to extract.Merge organic layer, with salt solution (1x100mL) washing, dry (MgSO
4), filter, then concentrating under reduced pressure.Resistates is carried out purifying by silica gel chromatography (hexane, ethyl acetate), obtains 2-(2-methoxyl group-4-nitrophenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane (15.28g, 54.7mmol, 64% productive rate), it is brown solid.Parent ion is not observed in MS.
1hNMR (400MHz, chloroform-d) δ 7.79 (d, J=1.0Hz, 2H), 7.67 (s, 1H), 3.93 (s, 3H), 1.38 (s, 12H).
Part B .4-bromo-nicotinic acid methyl esters
In room temperature in a nitrogen atmosphere, to 4-bromo-nicotinic acid (2.81g, 13.91mmol) at CH
2cl
2(20mL) add oxalyl chloride (3.04mL, 34.8mmol) in the solution in, then drip DMF (0.33mL).Observe bubbling and by reaction mixture at stirring at room temperature 45min.Solution is cooled to 0 DEG C, lasts 5min and add methyl alcohol (5.63mL, 139mmol), then stir 10min.Decompression concentrated solution, to be absorbed in resistates in EtOAc and to alkalize with saturated sodium bicarbonate aqueous solution.Solution EtOAc (3x20mL) extracts.By organism salt solution (1x20mL) washing merged, dry (MgSO
4), filter, then concentrating under reduced pressure, obtain 4-bromo-nicotinic acid methyl esters (2.7g, 11.87mmol, 85% productive rate), it is brown oil, is not further purified and can carries out downwards.
1hNMR (400MHz, chloroform-d) δ 9.05 (s, 1H), 8.60 (d, J=5.5Hz, 1H), 7.55-7.32 (m, 1H), 4.03-3.95 (m, 3H); LCMS (ESI) m/e216.1,218.1Br pattern [(M+H)
+, C
7h
7brNO
2calculated value 216.0].
C part .4-(2-methoxyl group-4-nitrophenyl) nicotinic acid methyl ester
4-bromo-nicotinic acid methyl esters (1.35g is added in sealable flask, 6.25mmol), cesium carbonate (4.07g, 12.50mmol), tetra-triphenylphosphine palladium (0) (0.722g, 0.625mmol) with 2-(2-methoxyl group-4-nitrophenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane (1.744g, 6.25mmol).Add and carry out degassed diox (14.7mL) and water (3.68mL) by nitrogen bubble by solution 5min and bottle is sealed.Solution is heated to 80 DEG C in ice bath and keeps 5h.Mixture is cooled to room temperature, through diatomite
filter, then concentrating under reduced pressure.Resistates is carried out purifying via silica gel chromatography (EtOAc: hexane), and obtain 4-(2-methoxyl group-4-nitrophenyl) nicotinic acid methyl ester (1.9g, 5.93mmol, 95% productive rate), it is brown oil.
1hNMR (400MHz, chloroform-d) δ 9.15 (d, J=0.5Hz, 1H), 8.82 (d, J=5.0Hz, 1H), 7.98 (dd, J=8.3,2.0Hz, 1H), 7.79 (d, J=2.0Hz, 1H), 7.38 (d, J=8.3Hz, 1H), 7.24 (dd, J=5.0,0.5Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H); LCMS (ESI) m/e289.1 [(M+H)
+, C
14h
13n
2o
5calculated value 289.1].
D part .8-nitro-5H-chromene also [3,4-c] pyridine-5-ketone
In 4-(2-methoxyl group-4-nitrophenyl) solution of nicotinic acid methyl ester (1.71g, 5.93mmol) in DCM (29.7ml), boron tribromide (2.242ml, 23.72mmol) is dripped at 0 DEG C.Solution is warmed to room temperature and stirs 14h.Solution be cooled to 0 DEG C and use methyl alcohol (~ 10mL) cancellation.Via the solid that collected by vacuum filtration is formed.Obtain 8-nitro-5H-chromene also [3,4-c] pyridine-5-ketone (1.43g, 5.61mmol, 95% productive rate), it is light brown amorphous solid, is not further purified and can carries out downwards.LCMS (ESI) m/e243.1, [(M+H)
+, C
12h
7n
2o
4calculated value 243.0].
E part .8-amino-5H-chromene also [3,4-c] pyridine-5-ketone
To 8-nitro-5H-chromene also [3,4-c] pyridine-5-ketone hydrobromate (800mg, 2.476mmol) and the solution of palladium/carbon (10wt%) (26.3mg, 0.248mmol) in EtOH (2.4mL) jolting 1.5h under 40psiH2.By mixture through diatomite
filter, then concentrating under reduced pressure filtrate.Obtain 8-amino-5H-chromene also [3,4-c] pyridine-5-ketone tfa salt (632mg, 1.84mmol, 74% productive rate), it is orange amorphous solid.LCMS (ESI) m/e213.2, [(M+H)
+, C
12h
9n
2o
2calculated value 213.1].
F part. (S)-(4-methyl isophthalic acid-oxo-1-((5-oxo-5H-chromene is [3,4-c] pyridine-8-base also) is amino) penta-2-base) t-butyl carbamate
To the 8-amino-5H-chromene being cooled to 0 DEG C also [3,4-c] pyridine-5-ketone tfa salt (63mg, 0.193mmol), (S)-2-((tert-butoxycarbonyl) is amino)-4-methylvaleric acid, water (53.0mg, 0.212mmol) with DIEA (169 μ l, HATU (110mg, 0.290mmol) is added in solution 0.966mmol) in DCM (3862 μ l).Solution is warmed to room temperature and stirs 12h.Resistates is also carried out purifying by reversed-phase HPLC (10%-100%MeOH/H2O/0.1%TFA) by concentrating under reduced pressure reaction mixture.Obtain (S)-(4-methyl isophthalic acid-oxo-1-((5-oxo-5H-chromene also [3,4-c] pyridine-8-base) amino) penta-2-base) t-butyl carbamate 2TFA salt (17mg, 0.028mmol, 15% productive rate), it is Light brown solid.
1hNMR (400MHz, methyl alcohol-d4) δ 9.41 (br.s., 1H), 8.91 (br.s., 1H), 8.34-8.23 (m, 2H), 7.91 (d, J=2.3Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 4.34-4.22 (m, 1H), 1.88-1.72 (m, 2H), 1.46 (d, J=7.5Hz, 9H), 1.00 (dd, J=6.7,1.4Hz, 6H); LCMS (ESI) m/e426.2 [(M+H)+, C
23h
28n
3o
5calculated value 426.2].
G part. (S)-2-amino-4-methyl-N-(5-oxo-5H-chromene is [3,4-c] pyridine-8-base also) valeramide
By (S)-(4-methyl isophthalic acid-oxo-1-((5-oxo-5H-chromene also [3,4-c] pyridine-8-base) amino) penta-2-base) t-butyl carbamate 2TFA salt (6mg, solution 0.014mmol) in hydrogenchloride (solution of 2N in ether) (176 μ l, 0.353mmol) is at stirring at room temperature 2h.Resistates is also passed through reversed-phase HPLC (5%-70%MeOH/H by concentrating under reduced pressure mixture
2o/0.1%TFA) purifying is carried out.Obtain (S)-2-amino-4-methyl-N-(5-oxo-5H-chromene is [3,4-c] pyridine-8-base also) valeramide (3.4mg, 5.84 μMs, 41% productive rate), it is yellow film shape thing.
1hNMR (400MHz, methyl alcohol-d
4) δ 9.41 (s, 1H), 8.91 (d, J=5.5Hz, 1H), 8.33 (d, J=8.8Hz, 1H), 8.28 (d, J=5.5Hz, 1H), 7.95 (d, J=2.3Hz, 1H), 7.62 (dd, J=8.8,2.0Hz, 1H), 4.09 (t, J=7.2Hz, 1H), 1.87-1.81 (m, 2H), 1.82-1.75 (m, 1H), 1.07 (d, J=2.3Hz, 3H), 1.06 (d, J=2.5Hz, 3H); LCMS (ESI) m/e326.2 [(M+H)+, C
18h
20n
3o
3calculated value 326.2].
Embodiment 12
5H-chromene is [3,4-c] pyridine-8-aminocarbamic acid peopentyl ester also
Part A. (the bromo-3-p-methoxy-phenyl of 4-) t-butyl carbamate
In THF (1.5L), in stirred solution, BOC is added to the bromo-3-anisidine (50g, 247mmol) of 4-
2o (0.069L, 297mmol) and triethylamine (0.045L, 322mmol), be then heated to the 12h that refluxes by gained reaction mixture.Reaction mixture is cooled to room temperature and decompression removing THF.Resistates is absorbed in ethyl acetate (500mL), with water (250mL) and salt solution (250mL) washing, then with anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is carried out purifying by silica gel chromatography (petrol ether/ethyl acetate), and obtain (the bromo-3-p-methoxy-phenyl of 4-) t-butyl carbamate (60g, 193mmol, 78% productive rate), it is light tan solid.
1hNMR (400MHz, DMSO-d
6) δ 9.48 (s, 1H), 7.40 (d, J=8.4Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 6.96 (dd, J=8.4Hz, J=2.4Hz, 1H), 3.79 (s, 3H), 1.48 (s, 9H); LCMS (method E) (ESI) m/e302.0,304.0Br pattern [(M+H)
+, C
12h
17brNO
3calculated value 302.0].
Part B. (3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-base) phenyl) t-butyl carbamate
In DMF (750mL), carry out purging 10min through stirred solution N2 to (the bromo-3-p-methoxy-phenyl of 4-) t-butyl carbamate (25g, 83mmol), then add potassium acetate (24.36g with portion, 248mmol) with 4,4,4', 4', 5,5,5', 5'-prestox-2,2'-bis-(1,3,2-dioxaborolan alkane) (31.5g, 124mmol).Solution is used nitrogen purging 10min, then add PdCl
2(dppf)-CH
2cl
2solution N2 is also purged 5min by adducts (6.76g, 8.27mmol) again.Then reaction mixture is heated 12h at 100 DEG C.Mixture is cooled to room temperature and decompression removing DMF.Resistates is absorbed in ethyl acetate (800mL) and also uses water (200mL), salt solution (200mL), with anhydrous sodium sulfate drying, then concentrating under reduced pressure, obtains light brown (brownish) oily matter.Thick material is carried out purifying by silica gel chromatography (petrol ether/ethyl acetate), obtains (3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-base) phenyl) t-butyl carbamate.
1HNMR(400MHz,DMSO-d
6)δ9.45(s,1H),7.42(d,J＝8.0Hz,1H),7.17(d,J＝1.6Hz,1H),7.00(dd,J＝8.0Hz,J＝1.6Hz,1H),3.66(s,3H),1.47(s,9H),1.24(s,12H)。
C part .4-chloropyridine-3-formaldehyde
In anhydrous THF (150mL), in stirred solution, N-butyllithium (7.33g, 114mmol) is dripped to Diisopropylamine (18.83mL, 132mmol) at-78 DEG C.Complete and after adding, temperature of reaction is risen to 0 DEG C and by solution stirring 1h.Make reaction mixture be back to-78 DEG C again and last 15min to add the solution of 4-chloropyridine (10g, 88mmol) in THF (100ml).Complete after adding and reaction mixture is stirred 1h at-78 DEG C, then add DMF (20mL) and by reaction mixture at stirring at room temperature 30min.Reaction mixture is also extracted by ethyl acetate (3x150mL) by water (100mL) cancellation carefully.The organics washed with water (100mL) merged, salt solution (100mL) are washed, with anhydrous sodium sulfate drying, then concentrating under reduced pressure.Resistates is carried out purifying by silica gel chromatography (petrol ether/ethyl acetate), and obtain 4-chloropyridine-3-formaldehyde (8.0g, 56.5mmol, 64% productive rate), it is colorless solid.
1hNMR (400MHz, CDCl
3) δ 10.51 (s, 1H), 9.05 (s, 1H), 8.68 (d, J=5.6Hz, 1H), 7.44 (d, J=5.6Hz, 1H); LCMS (ESI) m/e142.2 [(M+H)
+, C
6h
5clNO calculated value 142.0].
D part. (4-(3-(hydroxymethyl) pyridin-4-yl)-3-p-methoxy-phenyl) t-butyl carbamate
By (3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-base) phenyl) t-butyl carbamate (12.95g, 37.1mmol) in Isosorbide-5-Nitrae-diox (300mL) and water (50mL) through stirred solution nitrogen purging 10min.Add 4-chloropyridine-3-formaldehyde (5g, 35.3mmol) and Tripotassium phosphate (30.0g, 141mmol) and by solution N2 degassed 5min again.Add PdCl
2(dppf)-CH
2cl
2adducts (2.308g, 2.83mmol) by solution N
2degassed 5min again.In a nitrogen atmosphere reaction mixture is heated 1h at 100 DEG C.Mixture is cooled to room temperature, with water (100mL) cancellation also with ethyl acetate (3x150mL) extraction.The organic layers with water (100mL) merged, salt solution (100mL) are washed, with anhydrous sodium sulfate drying, then concentrating under reduced pressure.Thick material is carried out purifying by silica gel chromatography (petrol ether/ethyl acetate); obtain (4-(3-formylpyridine-4-base)-3-p-methoxy-phenyl) t-butyl carbamate (9.0g; 27.4mmol, 78% productive rate), it is colorless solid.
1hNMR (300MHz, DMSO-d
6) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.89 (s, 1H), 8.79 (d, J=5.1Hz, 1H), 7.41 (dd, J=7.2Hz, J=2.1Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 7.18 (dd, J=8.4Hz, J=2.1Hz, 1H), 3.67 (s, 3H), 1.50 (s, 9H); LCMS (ESI) m/e329.2 [(M+H)
+, C
18h
21n
2o
4calculated value 329.2].
E part. (4-(3-(hydroxymethyl) pyridin-4-yl)-3-p-methoxy-phenyl) t-butyl carbamate
At 0 DEG C at N
2under; to (4-(3-formylpyridine-4-base)-3-p-methoxy-phenyl) t-butyl carbamate (8.0g; in stirred solution, sodium borohydride (1.11g, 29.2mmol) is added 24.36mmol) in methyl alcohol (140mL).Complete after adding, by gained mixture at stirring at room temperature 1h.By reaction mixture use water (150mL) cancellation, decompression removing methyl alcohol, then extracts solution with ethyl acetate (2x200mL).The organic layers with water (100mL) merged, salt solution (100mL) are washed, with dried over sodium sulfate, then concentrating under reduced pressure.By 50% ethyl acetate/petroleum ether (50mL) washing of crude solid heat, then via collected by vacuum filtration solid, obtain (4-(3-(hydroxymethyl) pyridin-4-yl)-3-p-methoxy-phenyl) t-butyl carbamate (6.0g, 17.8mmol, 73% productive rate), it is pale solid.
1HNMR(300MHz,DMSO-d
6)δ9.50(s,1H),8.67(s,1H),8.42(d,J＝4.8Hz,1H),7.37(d,J＝1.2Hz,1H),7.11–7.02(m,3H),5.13(d,J＝5.4Hz,1H),4.32(d,J＝5.4Hz,2H),3.67(s,3H),1.49(s,9H)。
F part .5H-chromene is [3,4-c] pyridine-8-amine also
To (4-(3-(hydroxymethyl) pyridin-4-yl)-3-p-methoxy-phenyl) t-butyl carbamate (5.0g, 15.13mmol) at water (0.822ml, add Hydrogen bromide (63%) in solution 15.13mmol), then solution is heated 14h at 100 DEG C.Concentrating under reduced pressure reaction mixture.Resistates is absorbed in DCM (100mL) and water (100mL), then with the alkalization of 1N sodium hydroxide.Solution DCM (2x300mL) extracts.The organic layers with water (100mL) merged, salt solution (100mL) are washed, with dried over sodium sulfate, then concentrating under reduced pressure.Thick solid 20% ethyl acetate/petroleum ether washed, then drying under reduced pressure, obtain 5H-chromene also [3,4-c] pyridine-8-amine (2.0g, 9.99mmol, 66% productive rate), it is yellow solid.
1HNMR(400MHz,DMSO-d
6)δ8.40(d,J＝5.2Hz,1H),8.31(s,1H),7.57(d,J＝6.3Hz,1H),7.51(d,J＝5.2Hz,1H),6.33(dd,J＝8.4Hz,J＝2.0Hz,1H),6.15(d,J＝2.0Hz,1H),5.06(s,2H)。
G part .5H-chromene is [3,4-c] pyridine-8-aminocarbamic acid peopentyl ester also
To 5H-chromene also [3,4-c] pyridine-8-amine (13.8mg, DIEA (48 μ L, 0.277mmol) and neopentyl chloroformate (21 μ L, 1.39mmol) is added in solution 0.069mmol) in DCE (1mL).By mixture at stirring at room temperature 12h.Concentrating under reduced pressure mixture via reversed-phase HPLC (acetonitrile: the water with 20-mM ammonium hydroxide) purifying.Obtain 5H-chromene also [3,4-c] pyridine-8-aminocarbamic acid peopentyl ester (16.5mg, 0.053mmol, 77% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 9.87 (s, 1H), 8.51 (d, J=5.2Hz, 1H), 8.42 (s, 1H), 7.85 (d, J=8.5Hz, 1H), 7.69 (d, J=5.2Hz, 1H), 7.23 (s, 1H), 7.20 (d, J=8.5Hz, 1H), 5.17 (s, 2H), 3.81 (s, 2H), 0.94 (s, 9H); LCMS (ESI) m/e313.3 [(M+H)
+, C
18h
21n
3o
3calculated value 313.2].
Embodiment 13
1-(5H-chromene is [3,4-c] pyridine-8-base also)-3-cyclohexyl urea
Follow the scheme identical with described in embodiment 12, in G part, use cyclohexyl carboxyamide chlorine, prepare title compound, obtain 1-(5H-chromene also [3,4-c] pyridine-8-base)-3-cyclohexyl urea (2.7mg, 8.35 μm of ol, 12% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 8.62 (s, 1H), 8.48 (d, J=5.5Hz, 1H), 8.39 (s, 1H), 7.78 (d, J=8.9Hz, 1H), 7.65 (d, J=5.2Hz, 1H), 7.22 (s, 1H), 7.00 (d, J=8.5Hz, 1H), 6.19 (d, J=7.9Hz, 1H), 5.14 (s, 2H), 3.48 – 3.30 (m, 1H), 1.85-1.42 (m, 4H), 1.36-0.95 (m, 6H); LCMS (ESI) m/e324.3 [(M+H)
+, C
19h
22n
3o
2calculated value 324.2].
Embodiment 14
N-(5H-chromene is [3,4-c] pyridine-8-base also) penta-4-alkynyl amide
Follow the scheme identical with described in embodiment 12, use penta-4-acetylenic acid (9.81mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base) penta-4-alkynyl amide (9.6mg, 0.034mmol, 69% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.22 (s, 1H), 8.53 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.89 (d, J=8.5Hz, 1H), 7.71 (d, J=4.9Hz, 1H), 7.42 (s, 1H), 7.28 (d, J=8.2Hz, 1H), 5.19 (s, 2H), 2.80 (s, 1H), 2.62-2.40 (m, 4H); LCMS (ESI) m/e279.2 [(M+H)
+, C
17h
15n
2o
2calculated value 279.1].
Embodiment 15
N-(5H-chromene is [3,4-c] pyridine-8-base also) valeramide
Follow the scheme identical with described in embodiment 12, use valeric acid (10.21mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) valeramide (13.0mg, 0.046mmol, 92% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.18 (br.s., 1H), 8.48 (br.s., 1H), 8.39 (br.s., 1H), 7.83 (d, J=8.2Hz, 1H), 7.68 (br.s., 1H), 7.38 (br.s., 1H), 7.24 (d, J=7.3Hz, 1H), 5.15 (br.s., 2H), 2.29 (d, J=6.4Hz, 2H), 1.53 (d, J=6.4Hz, 2H), 1.28 (d, J=6.7Hz, 2H), 0.86 (dt, J=7.1,3.6Hz, 3H); LCMS (ESI) m/e283.2 [(M+H)
+, C
17h
19n
2o
2calculated value 283.1].
Embodiment 16
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-cyano group propionic acid amide
Follow the scheme identical with described in embodiment 12, use 3-cyanopropionic acid (9.91mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3-cyano group propionic acid amide (4.1mg, 0.015mmol, 29% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.34 (s, 1H), 8.53 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.90 (d, J=8.2Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.40 (s, 1H), 7.27 (d, J=8.2Hz, 1H), 5.19 (s, 2H), 2.73 (s, 4H); LCMS (ESI) m/e280.1 [(M+H)
+, C
16h
14n
3o
2calculated value 280.1].
Embodiment 17
N-(5H-chromene is [3,4-c] pyridine-8-base also) ethanamide
Follow the scheme identical with described in embodiment 12, use acetic acid (6.00mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) ethanamide (9.4mg, 0.039mmol, 78% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.16 (br.s., 1H), 8.52 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.91-7.83 (m, 1H), 7.70 (d, J=5.2Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.25 (dd, J=8.4,2.0Hz, 1H), 5.28-5.03 (m, 2H), 2.19-1.92 (m, 3H); LCMS (ESI) m/e241.2 [(M+H)
+, C
14h
13n
2o
2calculated value 241.1].
Embodiment 18
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-methoxypropionamide
Follow the scheme identical with described in embodiment 12, use 3-methoxypropionic acid (10.41mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3-methoxypropionamide (11.3mg, 0.040mmol, 79% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.18 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.71 (d, J=4.9Hz, 1H), 7.43 (d, J=1.8Hz, 1H), 7.28 (dd, J=8.5,1.8Hz, 1H), 5.19 (s, 2H), 3.62 (t, J=6.1Hz, 2H), 3.25 (s, 3H), 2.57 (t, J=6.1Hz, 2H); LCMS (ESI) m/e285.3 [(M+H)
+, C
16h
17n
2o
3calculated value 285.1].
Embodiment 19
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-hydroxypropanamide
Follow the scheme identical with described in embodiment 12, use 3-hydroxy-propionic acid (9.01mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3-hydroxypropanamide (2.3mg, 8.51 μm of ol, 17% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.15 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.5Hz, 1H), 5.19 (s, 2H), 4.74 (br.s., 1H), 3.72 (t, J=5.6Hz, 2H), 2.49-2.45 (m, 2H); LCMS (ESI) m/e271.2 [(M+H)
+, C
15h
15n
2o
3calculated value 271.1].
Embodiment 20
N-(5H-chromene is [3,4-c] pyridine-8-base also)-1-cyano group cyclopropane carboxamide
Follow the scheme identical with described in embodiment 12, use 1-cyano group cyclopropane-carboxylic acid (11.11mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-1-cyano group cyclopropane carboxamide (6.3mg, 0.022mmol, 43% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.20 (br.s., 1H), 8.55 (d, J=4.9Hz, 1H), 8.46 (s, 1H), 7.92 (d, J=7.9Hz, 1H), 7.74 (d, J=4.9Hz, 1H), 7.41-7.34 (m, 2H), 5.21 (s, 2H), 1.70 (s, 4H); LCMS (ESI) m/e292.2 [(M+H)
+, C
17h
14n
3o
2calculated value 292.1].
Embodiment 21
N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-sulfamyl butyramide
Follow the scheme identical with described in embodiment 12; use 4-sulfamyl butyric acid (16.72mg; 0.100mmol); prepare title compound; obtain N-(5H-chromene also [3; 4-c] pyridine-8-base)-4-sulfamyl butyramide (2.7mg, 7.77 μm of ol, 16% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.20 (br.s., 1H), 8.53 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.2Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.43 (s, 1H), 7.28 (d, J=8.2Hz, 1H), 6.82 (br.s., 2H), 5.19 (s, 2H), 3.10-2.99 (m, 2H), 2.54 – 2.52 (m, 2H), 2.06-1.95 (m, 2H); LCMS (ESI) m/e348.2 [(M+H)
+, C
16h
18n
3o
4s calculated value 348.1].
Embodiment 22
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-(2-oxo-pyrrolidine-1-base) propionic acid amide
Follow the scheme identical with described in embodiment 12, use 3-(2-oxo-pyrrolidine-1-base) propionic acid (15.72mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3-(2-oxo-pyrrolidine-1-base) propionic acid amide (11.9mg, 0.035mmol, 71% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.23 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.45 (s, 1H), 7.89 (d, J=8.2Hz, 1H), 7.71 (d, J=5.5Hz, 1H), 7.41 (d, J=1.8Hz, 1H), 7.26 (dd, J=8.4,2.0Hz, 1H), 5.19 (s, 2H), 3.48 (t, J=6.9Hz, 2H), 3.35-3.31 (m, 2H), 2.55 (t, J=7.0Hz, 2H), 2.23-2.17 (m, 2H), 1.90 (quintet, J=7.6Hz, 2H); LCMS (ESI) m/e338.3 [(M+H)
+, C
19h
20n
3o
3calculated value 338.2].
Embodiment 23
N-(5H-chromene is [3,4-c] pyridine-8-base also) cyclohexane carboxamide
Follow the scheme identical with described in embodiment 12, use naphthenic acid (12.82mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base) cyclohexane carboxamide (13.7mg, 0.044mmol, 89% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.03 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.70 (d, J=4.9Hz, 1H), 7.44 (s, 1H), 7.30 (d, J=7.9Hz, 1H), 5.18 (s, 2H), 2.33 (t, J=11.7Hz, 1H), 1.88-1.72 (m, 4H), 1.66 (d, J=11.3Hz, 1H), 1.48-1.35 (m, 2H), 1.32-1.13 (m, 3H); LCMS (ESI) m/e309.3 [(M+H)
+, C
19h
21n
2o
2calculated value 309.2].
Embodiment 24
N-(5H-chromene is [3,4-c] pyridine-8-base also) isobutyramide
Follow the scheme identical with described in embodiment 12, use isopropylformic acid (8.81mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) isobutyramide (11.5mg, 0.043mmol, 86% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.05 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.44 (d, J=1.5Hz, 1H), 7.36-7.23 (m, 1H), 5.19 (s, 2H), 2.60 (quintet, J=6.9Hz, 1H), 1.11 (d, J=6.7Hz, 6H); LCMS (ESI) m/e269.2 [(M+H)
+, C
16h
17n
2o
2calculated value 269.1].
Embodiment 25
N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-malonamide nitrile
Follow the scheme identical with described in embodiment 12, use 2-cyanoacetic acid (8.51mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-2-malonamide nitrile (10.7mg, 0.040mmol, 81% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.52 (br.s., 1H), 8.55 (d, J=5.2Hz, 1H), 8.46 (s, 1H), 7.93 (d, J=8.5Hz, 1H), 7.73 (d, J=4.9Hz, 1H), 7.35 (s, 1H), 7.24 (d, J=8.2Hz, 1H), 5.21 (s, 2H), 3.94 (s, 2H); LCMS (ESI) m/e266.2 [(M+H)
+, C
15h
12n
3o
2calculated value 266.1].
Embodiment 26
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3,3-amide dimethyl butyrates
Follow the scheme identical with described in embodiment 12, use 3,3-acid dimethyl (11.61mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3,3-amide dimethyl butyrate (11.4mg, 0.038mmol, 77% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.01 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.70 (d, J=4.9Hz, 1H), 7.44 (s, 1H), 7.28 (d, J=8.5Hz, 1H), 5.19 (s, 2H), 2.21 (s, 2H) 1.03 (s, 9H); LCMS (ESI) m/e297.9 [(M+H)
+, C
18h
21n
2o
2calculated value 297.1].
Embodiment 27
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-methylbutyryl amine
Follow the scheme identical with described in embodiment 12, use 3 Methylbutanoic acid (10.21mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-3-methylbutyryl amine (11.3mg, 0.040mmol, 80% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.08 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.70 (d, J=5.2Hz, 1H), 7.44 (s, 1H), 7.28 (d, J=8.9Hz, 1H), 5.19 (s, 2H), 2.21 (d, J=7.0Hz, 2H), 2.08 (dt, J=13.6,6.6Hz, 1H), 1.00-0.82 (m, 6H); LCMS (ESI) m/e283.2 [(M+H)
+, C
17h
19n
2o
2calculated value 283.1].
Embodiment 28
N-(5H-chromene is [3,4-c] pyridine-8-base also) propionic acid amide
Follow the scheme identical with described in embodiment 12, use propionic acid (7.41mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) propionic acid amide (10.0mg, 0.039mmol, 79% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.08 (br.s., 1H), 8.53 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.70 (d, J=5.2Hz, 1H), 7.43 (br.s., 1H), 7.28 (d, J=8.2Hz, 1H), 5.19 (s, 2H), 2.51 (br.s., 3H), 2.40-2.28 (m, 2H); LCMS (ESI) m/e255.2 [(M+H)
+, C
15h
15n
2o
2calculated value 255.1].
Embodiment 29
4-((5H-chromene is [3,4-c] pyridine-8-base also) is amino)-4-oxobutyrate
Follow the scheme identical with described in embodiment 12, use 4-methoxyl group-4-ketobutyric acid (13.21mg, 0.100mmol), prepare title compound, obtain 4-((5H-chromene also [3,4-c] pyridine-8-base) amino)-4-oxobutyrate (9.7mg, 0.031mmol, 62% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.22 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.40 (s, 1H), 7.27 (d, J=8.2Hz, 1H), 5.19 (s, 2H), 3.61 (s, 3H), 2.68-2.58 (m, 4H); LCMS (ESI) m/e313.2 [(M+H)
+, C
17h
17n
2o
4calculated value 313.1].
Embodiment 30
N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide
Follow the scheme identical with described in embodiment 12, use 4-methylvaleric acid (11.61mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-4-methylpentanamide (7.2mg, 0.024mmol, 49% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.10 (br.s., 1H), 8.52 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.87 (dd, J=8.5,3.1Hz, 1H), 7.73-7.67 (m, 1H), 7.42 (d, J=2.1Hz, 1H), 7.27 (dd, J=8.4,2.0Hz, 1H), 5.19 (d, J=3.1Hz, 2H), 2.38-2.27 (m, 2H), 1.56 (dt, J=13.3,6.5Hz, 1H), 1.53-1.44 (m, 2H), 0.90 (dd, J=6.4,3.1Hz, 6H); LCMS (ESI) m/e297.3 [(M+H)
+, calculated value C
18h
21n
2o
2297.2].
Embodiment 31
N-(5H-chromene is [3,4-c] pyridine-8-base also) butyramide
Follow the scheme identical with described in embodiment 12, use butyric acid (8.81mg, 0.100mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) butyramide (10.9mg, 0.041mmol, 81% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 10.10 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.70 (d, J=5.2Hz, 1H), 7.43 (s, 1H), 7.28 (d, J=7.6Hz, 1H), 5.18 (s, 2H), 2.51 (br.s., 4H), 2.31 (t, J=7.3Hz, 2H), 1.72-1.44 (m, 2H); LCMS (ESI) m/e269.2 [(M+H)
+, C
16h
17n
2o
2calculated value 269.1].
Embodiment 32
N-(5H-chromene is [3,4-c] pyridine-8-base also) pivaloyl amine
Follow the scheme identical with described in embodiment 12, use trimethylacetic acid (5.11mg, 0.050mmol), prepare title compound, obtain N-(5H-chromene is [3,4-c] pyridine-8-base also) pivaloyl amine (8.2mg, 0.029mmol, 58% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 9.37 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.44 (s, 1H), 7.88 (d, J=8.5Hz, 1H), 7.72 (d, J=4.9Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=8.5Hz, 1H), 5.19 (s, 2H), 1.24 (s, 9H); LCMS (ESI) m/e283.0 [(M+H)
+, C
17h
19n
2o
2calculated value 283.1].
Embodiment 33
N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-(dimethylamino) ethanamide
Follow the scheme identical with described in embodiment 12, use 2-(dimethylamino) acetic acid (5.16mg, 0.050mmol), prepare title compound, obtain N-(5H-chromene also [3,4-c] pyridine-8-base)-2-(dimethylamino) ethanamide (8.3mg, 0.029mmol, 59% productive rate).
1hNMR (500MHz, DMSO-d
6) δ 9.96 (br.s., 1H), 8.52 (d, J=4.9Hz, 1H), 8.43 (s, 1H), 7.87 (d, J=8.5Hz, 1H), 7.71 (d, J=5.2Hz, 1H), 7.48 (d, J=1.8Hz, 1H), 7.37 (dd, J=8.5,1.8Hz, 1H), 5.18 (s, 2H), 3.08 (s, 2H), 2.26 (s, 6H); LCMS (ESI) m/e284.2 [(M+H)
+, C
16h
18n
3o
2calculated value 284.1].
Embodiment 34
N-(the bromo-5H-chromene of 9-is [3,4-c] pyridine-8-base also) valeramide
By N-(5H-chromene also [3,4-c] pyridine-8-base) valeramide (10mg, 0.035mmol) be heated to 90 DEG C with the mixture of 1-bromine tetramethyleneimine-2,5-diketone (6.93mg, 0.039mmol) in acetonitrile (708 μ l) and keep 1h.Mixture is cooled to room temperature and carries out purifying via silica gel chromatography (EtOAc/ hexane), obtain N-(the bromo-5H-chromene of 9-is [3,4-c] pyridine-8-base also) valeramide (6mg, 0.016mmol, 45.5% productive rate), it is colorless solid.
1hNMR (400MHz, methyl alcohol-d
4) δ 8.51 (d, J=5.5Hz, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.74 (d, J=5.5Hz, 1H), 7.57 (s, 1H), 5.22 (s, 2H), 4.63 (s, 1H), 2.49 (t, J=7.5Hz, 2H), 1.78-1.66 (m, 2H), 1.45 (dq, J=7.5,7.3Hz, 2H), 0.99 (t, J=7.3Hz, 3H); LCMS (ESI) m/e361.1,363.1Br pattern [(M+H)
+, C
17h
18brN
2o
2calculated value 361.1].
Embodiment 35
(S)-N-(2-acetylaminohydroxyphenylarsonic acid 5H-chromene is [3,4-c] pyridine-8-base also)-2-amino-4-methylpentanamide
Part A .2-(the fluoro-4-nitrophenyl of 2-)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane
By the iodo-4-oil of mirbane of fluoro-for 2-1-(2g, 7.49mmol), potassium acetate (2.205g, 22.47mmol) He two (tetramethyl ethylene ketone conjunction) two boron (solution N in 2.283g, 8.99mmol) diox (21.10ml)
2purge 5min.Add 1,1'-bis-(diphenylphosphino) ferrocene palladium chloride (II), toluene (0.616g, 0.749mmol) by solution N
2purge 5min again.Mixture is heated 2h at 80 DEG C in oil bath.Brown mixture is cooled room temperature and via the diatomite with EtOAc wash-out
filter.Resistates is carried out purifying via silica gel chromatography (10%-20%EtOAc/ hexane).Obtain 2-(the fluoro-4-nitrophenyl of 2-)-4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane (1.3g, 4.87mmol, 65% productive rate), it is faint yellow solid.
1hNMR (400MHz, methyl alcohol-d
4) δ 8.07 – 8.04 (m, 1H), 7.97-7.91 (m, 1H), 7.78-7.70 (m, 1H), 1.21 (s, 12H).
The bromo-4-chloropyridine of part B .5--2-amine
By 4-chloropyridine-2-amine (2.268g, 17.64mmol) and NBS (3.14g, 17.64mmol), the solution in acetonitrile (176ml) is at stirring at room temperature 12h.Solution with water is diluted and uses EtOAc (3X100mL) to extract.The organism merged is washed with salt solution (1X100mL); Dry (MgSO4), filter, then concentrating under reduced pressure, obtain the bromo-4-chloropyridine of 5--2-amine (4.28g, 13.62mmol, 77% productive rate), it is faint yellow solid.
1hNMR (400MHz, methyl alcohol-d4) δ 8.04 (s, 1H), 6.74 (s, 1H); LCMS (ESI) m/e207.0,209.0Br pattern [(M+H)
+, C
5h
5brClN
2calculated value 206.9].
C part .N-(the bromo-4-chloropyridine of 5--2-base) ethanamide
In the solution of 5-bromo-4-chloropyridine-2-amine (2.83g, 13.62mmol) in pyridine (34.1ml), Acetyl Chloride 98Min. (1.07ml, 14.98mmol) is added at 0 DEG C.Complete after adding, solution is warmed to room temperature and stirs 2h.Decompression removing excess pyridine.Resistates is diluted with EtOAc (75mL) and uses water (2X25mL) to wash.The water layer merged is extracted with EtOAc (2X25mL).By organism salt solution (1X20mL) washing merged, dry (MgSO4), filters, then concentrating under reduced pressure.Resistates is carried out purifying via silica gel chromatography (5%-70%EtOAc/ hexane), and obtain N-(the bromo-4-chloropyridine of 5--2-base) ethanamide (3.6g, 12.99mmol, 95% productive rate), it is yellowish-pink solid.
1hNMR (400MHz, chloroform-d) δ 8.43 (s, 1H), 8.38 (s, 1H), 7.98 (br.s., 1H), 2.23 (s, 3H); LCMS (ESI) m/e248.9,250.9Br pattern [(M+H)
+, C
7h
7brClN
2o calculated value 248.9].
D part .N-(the chloro-5-vinyl pyridine of 4--2-base) ethanamide
N-(the bromo-4-chloropyridine of 5--2-base) ethanamide (0.72g is added in sealable bottle, 2.89mmol), 2,4,6-triethylene basic ring three boroxane pyridine complex (0.903g, 3.75mmol), tetrakis triphenylphosphine palladium (0) (0.100g, 0.087mmol) with sodium carbonate (0.612g, 5.77mmol), then add toluene (5.18mL) and EtOH (0.829mL).By solution N
2degassed 5min, is then heated to 85 DEG C by bottle and keeps 16h.Mixture is cooled to room temperature and through the diatomite with EtOAc wash-out
filter.Decompression concentrated solution.Resistates is carried out purifying via silica gel chromatography (10%-40%EtOAc/ hexane), and obtain N-(the chloro-5-vinyl pyridine of 4--2-base) ethanamide (0.6g, 1.83mmol, 60% productive rate), it is yellowish-pink solid.
1hNMR (400MHz, chloroform-d) δ 8.41 (s, 1H), 8.30 (s, 1H), 8.13 (br.s., 1H), 7.01-6.87 (m, 1H), 5.77 (dd, J=17.8,0.8Hz, 1H), 5.42 (dd, J=11.2,0.9Hz, 1H), 2.23 (s, 3H); LCMS (ESI) m/e197.1 [(M+H)
+, C
9h
10clN
2o calculated value 197.1].
E part .N-(the chloro-5-formylpyridine of 4--2-base) ethanamide
To N-(the chloro-5-vinyl pyridine of the 4--2-base) ethanamide (568mg being cooled to 0 DEG C, 2.89mmol) He 2,6-lutidine (673 μ L, perosmic anhydride (2.5% solution) in 2-methyl-2-propanol (588mg is successively added in solution 5.78mmol) in diox (10.2mL) and water (2.3mL), 0.058mmol) with sodium periodate (2.47g, 11.56mmol).Gained mixture is stirred 3h at 0 DEG C.By reaction mixture use water (3mL) cancellation also with EtOAc (3X10mL) extraction.By organism salt solution (1X10mL) washing merged, dry (MgSO
4), filter, then concentrating under reduced pressure.Resistates is carried out purifying via silica gel chromatography (5%-70%EtOAc/ hexane), and obtain N-(the chloro-5-formylpyridine of 4--2-base) ethanamide (430mg, 2.057mmol, 71% productive rate), it is pale solid.
1hNMR (400MHz, chloroform-d) δ 10.38 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.33 (br.s., 1H), 2.28 (s, 3H); LCMS (ESI) m/e199.1 [(M+H)
+, C
8h
8clN
2o
2calculated value 199.1].
F part .N-(4-(the fluoro-4-nitrophenyl of 2-)-5-formylpyridine-2-base) ethanamide
By N-(the chloro-5-formylpyridine of 4--2-base) ethanamide (0.3g; 1.51mmol); 2-(the fluoro-4-nitrophenyl of 2-)-4; 4,5,5-tetramethyl--1; 3; (the mixture N2 in 0.984g, 3.02mmol) diox (4.83mL) and water (1.21mL) purges 10min for 2-dioxaborolan alkane (0.576g, 1.36mmol) and cesium carbonate.Add tetrakis triphenylphosphine palladium (0) (0.349g, 0.302mmol), mixture be heated to 95 DEG C and keep 12h.Resistates is carried out purifying via silica gel chromatography (20%-80%EtOAc/ hexane); obtain N-(4-(the fluoro-4-nitrophenyl of 2-)-5-formylpyridine-2-base) ethanamide (250mg; 0.742mmol, 49% productive rate), it is yellow solid.
1hNMR (500MHz, chloroform-d) δ 9.90 (d, J=2.0Hz, 1H), 8.87 (s, 1H), 8.59 (br.s., 1H), 8.31 (s, 1H), 8.20 (ddd, J=8.4,2.1,0.6Hz, 1H), 8.08 (dd, J=9.0,2.1Hz, 1H), 7.58 (dd, J=8.3,7.1Hz, 1H), 2.30 (s, 3H); LCMS (ESI) m/e304.1 [(M+H)
+, C
14h
11fN
3o
4calculated value 304.1].
G part .N-(4-(the fluoro-4-nitrophenyl of 2-)-5-(hydroxymethyl) pyridine-2-base) ethanamide
To N-(4-(the fluoro-4-nitrophenyl of the 2-)-5-formylpyridine-2-base) ethanamide (0.225g being cooled to 0 DEG C; sodium borohydride (0.028g, 0.742mmol) is added in solution 0.742mmol) in tetrahydrofuran (THF) (4.57mL) and methyl alcohol (1.14mL).Solution is warmed to room temperature and stirs 1h.Reaction mixture saturated sodium bicarbonate aqueous solution (5mL) cancellation is also extracted with EtOAc (3X10mL).By organism salt solution (1X10mL) washing merged, dry (MgSO4), filters, then concentrating under reduced pressure.Be not further purified and the N-obtained thus (4-(the fluoro-4-nitrophenyl of 2-)-5-(hydroxymethyl) pyridine-2-base) ethanamide can be carried out downwards.LCMS (ESI) m/e306.1 [(M+H)
+, C
14h
13fN
3o
4calculated value 306.1].
H part .N-(8-nitro-5H-chromene is [3,4-c] pyridine-2-base also) ethanamide
To N-(4-(the fluoro-4-nitrophenyl of 2-)-5-(hydroxymethyl) pyridine-2-base) ethanamide (0.227g, sodium hydride (dispersion of 60wt% in oil) (0.030g, 0.742mmol) is added in solution 0.742mmol) in THF (7.42mL).By mixture at stirring at room temperature 10h.By mixture use water (5mL) cancellation also with EtOAc (3X10mL) extraction.By organism salt solution (1X10mL) washing merged, dry (MgSO
4), filter, then concentrating under reduced pressure.Resistates is carried out purifying via silica gel chromatography (5%-100%EtOAc/ hexane), obtain N-(8-nitro-5H-chromene is [3,4-c] pyridine-2-base also) ethanamide (117mg, 0.390mmol, go through two step 53% productive rates), it is faint yellow solid.
1hNMR (400MHz, chloroform-d) δ 8.61 (m, 1H), 8.17 (br.s., 1H), 7.98 (m, 3H), 7.87 (m, 1H), 5.23 (s, 2H), 2.27 (s, 3H); LCMS (ESI) m/e286.1 [(M+H)
+, C
14h
12n
3o
4calculated value 286.1].
Part I.N-(8-amino-5H-chromene is [3,4-c] pyridine-2-base also) ethanamide
By N-(8-nitro-5H-chromene is [3,4-c] pyridine-2-base also) ethanamide (17mg, 0.060mmol) and the 10% palladium/solution of carbon (6.34mg, 0.060mmol) in EtOH jolting 2h under 40psi hydrogen.By mixture through the diatomite with EtOAc wash-out
filter and concentrating under reduced pressure.Be not further purified and material can be carried out downwards.Obtain N-(8-amino-5H-chromene is [3,4-c] pyridine-2-base also) ethanamide (14mg, 0.044mmol, 74% productive rate), it is yellow solid.
1hNMR (400MHz, chloroform-d) δ 7.97 (s, 1H), 7.57 (d, J=8.5Hz, 1H), 7.28 (s, 1H), 6.47 (dd, J=8.7,2.1Hz, 1H), 6.21 (d, J=2.3Hz, 1H), 5.07 (s, 2H), 2.29 (s, 3H); LCMS (ESI) m/e256.1 [(M+H)
+, C
14h
14n
3o
2calculated value 256.1].
Part J. (S)-(the chloro-4-methyl isophthalic acid-oxo penta of 1--2-base) carboxylamine (9H-fluorenes-9-base) methyl ester
To (S)-2-((((9H-fluorenes-9-base) methoxyl group) carbonyl) is amino)-4-methylvaleric acid (200mg, successively thionyl chloride (solution of 2M in DCM) (2830 μ L are dripped in solution 0.566mmol) in DCM (1132 μ L), 5.66mmol) with DMF (55.0 μ L, 0.71mmol).Then be heated to reflux through mixture and keep 1h.Then solution is cooled to room temperature and concentrating under reduced pressure.DCM (10mL) to be added in resistates and concentrating under reduced pressure (3X), remove excessive thionyl chloride.Be not further purified and acyl chlorides can be carried out downwards.Aliquot acyl chlorides methyl alcohol cancellation: LC/MS is met and forms methyl esters (methyl esters: LCMS (ESI) m/e368.8 [(M+H) via acyl chlorides
+, C
22h
26nO
4calculated value 368.2]).
Part K. (S)-(9H-fluorenes-9-base) methyl (1-((2-acetylaminohydroxyphenylarsonic acid 5H-chromene is [3,4-c] pyridine-8-base also) is amino)-4-methyl isophthalic acid-oxo penta-2-base) t-butyl carbamate
To N-(8-amino-5H-chromene also [3,4-c] pyridine-2-base) ethanamide (21.44mg, 0.084mmol) with DIEA (44.0 μ L,-(the chloro-4-methyl isophthalic acid-oxo penta of 1--2-base) carboxylamine (9H-fluorenes-9-base) methyl ester (31.2mg, 0.084mmol) solution in DMF (0.2mL) is added (S) in solution 0.252mmol) in DMF (840 μ L).By mixture at stirring at room temperature 12h.By thick material by reversed-phase HPLC (AcCN/H
2o/0.1%TFA) purifying is carried out, obtain (S)-(1-((2-acetylaminohydroxyphenylarsonic acid 5H-chromene also [3,4-c] pyridine-8-base) amino)-4-methyl isophthalic acid-oxo penta-2-base) carboxylamine (9H-fluorenes-9-base) methyl ester (25mg, 0.038mmol, go through two step 45% productive rates), it is yellow solid.
1hNMR (400MHz, chloroform-d) δ 12.78 (br.s., 1H), 8.78 (s, 1H), 8.65 (br.s., 1H), 7.89 (s, 1H), 7.81-7.72 (m, 3H), 7.58 (d, J=7.8Hz, 2H), 7.45 (d, J=2.0Hz, 1H), 7.44-7.39 (m, 2H), 7.37-7.28 (m, 3H), 7.15 (d, J=7.5Hz, 1H), 5.25 (d, J=6.0Hz, 1H), 5.09 (s, 2H), 4.52 (d, J=6.3Hz, 2H), 4.23 (t, J=6.3Hz, 1H), 2.37 (s, 3H), 1.83-1.56 (m, 3H), 0.99 (d, J=6.3Hz, 3H), 0.96 (d, J=5.5Hz, 3H), LCMS (ESI) m/e591.9 [(M+H)
+, C
35h
35n
4o
5calculated value 591.3].
Part L. (S)-N-(2-acetylaminohydroxyphenylarsonic acid 5H-chromene is [3,4-c] pyridine-8-base also)-2-amino-4-methylpentanamide
By (S)-(1-((2-acetylaminohydroxyphenylarsonic acid 5H-chromene also [3,4-c] pyridine-8-base) amino)-4-methyl isophthalic acid-oxo penta-2-base) carboxylamine (9H-fluorenes-9-base) methyl ester (8.2mg, 0.014mmol) and the solution of diethylamine (72.5 μ L, 0.694mmol) in acetonitrile (139 μ L) at stirring at room temperature 1.5h.Decompression concentrated solution.Thick material is carried out purifying by reversed-phase HPLC (AcCN/H2O/0.1%TFA), obtain (S)-N-(2-acetylaminohydroxyphenylarsonic acid 5H-chromene also [3,4-c] pyridine-8-base)-2-amino-4-methylpentanamide 2TFA salt (3.5mg, 5.28 μm ol, 38% productive rate), it is faint yellow tympan.
1hNMR (400MHz, methyl alcohol-d4) δ 8.18 (br.s., 1H), 8.04 (br.s., 1H), 7.87 (d, J=8.5Hz, 1H), 7.52 (d, J=1.8Hz, 1H), 7.35 (dd, J=8.5,2.3Hz, 1H), 5.20 (s, 2H), 4.04 (t, J=7.2Hz, 1H), 2.28 (br.s., 3H), 1.85-1.73 (m, 3H), 1.05 (d, J=6.3Hz, 6H); LCMS (ESI) m/e369.8 [(M+H)
+, C
20h
25n
4o
3calculated value 369.2].
Embodiment 36
(S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-phenyl-acetamides
Follow the scheme identical with described in embodiment 12; (S)-2-((tert-butoxycarbonyl) is amino)-2-phenylacetic acid (38.0mg is used in G part; 0.151mmol); prepare title compound; obtain (S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-phenyl-acetamides 2TFA salt (31.7mg, 0.056mmol; 56% productive rate), after deprotection, it is yellow solid.
1hNMR (400MHz, methyl alcohol-d
4) δ 8.80-8.60 (m, 2H), 8.25 (d, J=6.3Hz, 1H), 8.03 (d, J=8.8Hz, 1H), 7.68-7.56 (m, 3H), 7.55-7.45 (m, 3H), 7.36 (dd, J=8.7,2.1Hz, 1H), 5.35 (s, 2H), 5.17 (s, 1H); LCMS (ESI) m/e332.1 [(M+H)
+, C
20h
18n
3o
2calculated value 332.1].
Embodiment 37
(S)-N
1-(5H-chromene is [3,4-c] pyridine-8-base also)-2-diphenylphosphino ethane-1,2-diamines
To (the S)-2-amino-N-prepared as described in example 36 above (5H-chromene also [3,4-c] pyridine-8-base)-2-phenyl-acetamides (20mg, 0.060mmol) drip in solution in THF borine tetrahydrofuran complex (solution of 1M in THF) (72.4 μ l, 0.072mmol).Solution be heated to 50 DEG C and keep 3h.Reaction mixture is cooled to room temperature, stirs 30min with MeOH (~ 1mL) cancellation.Decompression concentrated solution.Resistates is carried out purifying by reversed-phase HPLC (solution of 10%-60%AcCN in H2O/0.1%TFA, lasts 25min), obtains (S)-N
1-(5H-chromene is [3,4-c] pyridine-8-base also)-2-diphenylphosphino ethane-1,2-diamine TFA salt (6mg, 0.014mmol, 23% productive rate), it is yellow oil.
1hNMR (400MHz, methyl alcohol-d4) d8.46 (d, J=6.3Hz, 1H), 8.44 (s, 1H), 8.00 (d, J=6.3Hz, 1H), 7.81 (d, J=9.0Hz, 1H), 7.57-7.41 (m, 5H), 6.54 (dd, J=8.8,2.3Hz, 1H), (6.31 d, J=2.3Hz, 1H), 5.24 (s, 2H), 4.53 (t, J=7.2Hz, 1H), 3.89-3.77 (m, 1H), 3.75-3.65 (m, 1H); LCMS (ESI) m/e318.1 [(M+H)
+, C
20h
20n
3o calculated value 318.2].
Method
AAK1 kinase assays
Measure in orifice plate of the U-shaped end 384.Final mensuration volume is 30 μ l, and it is prepared as follows: at mensuration damping fluid (10mMTris-HCLpH7.4,10mMMgCl
2, 0.01%Tween-20 and 1.0mMDTT) in add 15 μ l enzymes and substrate (Fluoresceinated peptide (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH
2and ATP) and test compounds.By being combined in the GST-Xa-hAAK1 and substrate that express in bacterium and test compounds carrys out initiation reaction.Reaction mixture is carried out termination reaction incubation at room temperature 3 hours by adding 60 μ 135mMEDTA damping fluids in each sample.CaliperLabChip3000 (Caliper, Hopkinton, MA) carrys out analyze reaction mixture by electrophoretic separation fluorogenic substrate and Phosphorylated products.By with through EDTA cancellation control reaction (100% suppresses) and only compare calculate suppression data containing vectorial reaction (0% suppresses).In mensuration, the final concentration of reagent is: ATP22 μM; (5-FAM)-Aha-KEEQSQITSQVTGQIGWR-NH
21.5 μM; GST-Xa-hAAKl3.5nM; And DMSO1.6%.Obtain dose response curve to determine the concentration (IC needed for suppression 50% kinase activity
50).Compound to be dissolved in dimethyl sulfoxide (DMSO) (DMSO) with 10mM and to evaluate 11 concentration.IC is drawn by nonlinear regression analysis
50value.
Based on the mensuration of HEK281 cell
HEK293F cell is cultivated in the substratum containing DMEM (Gibco, catalog number (Cat.No.) 11965), 10%FBS (SAFCBiosciences, catalog number (Cat.No.) 12103C) and 1 × GPS (L-glutamic acid, penicillin and Streptomycin sulphate).At first day, cell is coated on 10cm culture dish to make it when transfection for ~ 80% merges.To have an appointment in 10cm culture dish when transfection 1,200 ten thousand cells.At second day, with 48 μ gDNA and 144 μ lLipofectamine2000 (Invitrogen, catalog number (Cat.No.) 11668-019) each culture dish of transfection.DNA forms (every 10cm culture dish) by the mixture containing 3 μ gAAK1/HA/pIRES (the total length mankind, NCBI preservation NP_055726.2), 45 μ gFlag/AP2MI/pcDNA (the total length mankind) and 1.5mlOPTI-MEM.Lipofectamine2000 is made up of (every 10cm culture dish) the mixture containing 144 μ lLipofectamine2000 and 1.5mlOPTI-MEM.Each mixture to be transferred in independent 15ml pipe and incubation at room temperature 5 minutes, then to merge two kinds of mixtures and incubation at room temperature 20 minutes.Then sucking-off growth medium replace with 10mlDMEM+10%FBS (without GPS) from each 10cm culture plate.Finally, in each 10cm culture dish, add 3mlDNA/Lipofectamine mixture gently mixing, then by culture plate at 37 DEG C and 5%CO
2be incubated overnight.
At the 3rd day, with 100%DMSO with 1000 × final concentration diluted compounds, then carry out 3 times of serial dilutions to obtain 5 test concentrations altogether.Four kinds of compounds tested by every 10cm culture dish.Then each diluted chemical compound liquid of 1 μ l is aspirated in deep hole 96 orifice plate, in each hole, then add 500 μ 1DMEM+0.5%FBS to obtain each compound of 2 × final concentration.By simply drawing (now HEK293 cell be easy to depart from culture plate) by cell Eddy diffusion in 10cm culture dish, to be then transferred in 50ml tapered tube and by within centrifugal 5 minutes, carrying out sedimentation at 1000rpm.Then by cell mass Eddy diffusion in 2.75mlDMEM+0.5%FBS (every 10cm culture dish) and 100 μ l cell suspending liquids are transferred in each hole of 96 hole TC plates.Finally 2 × compound that 100 μ l DMEM+0.5%FBS dilute is added in the hole containing cell suspending liquid to obtain 1 × final concentration.Then by culture plate at 37 DEG C and 5%CO
2incubation 3 hours, is then transferred to cell suspending liquid in 12 pipe PCR bars from each hole.PCR bar is rotated with 1000rpm in suction nozzle holder and within 5 minutes, lumps to make cell, then by draw but not disturbance cell mass removes substratum.
In order to prepare immunoblotting assay (WesternBlotanalysis), by cell mass Eddy diffusion in 40 μ l1 × LDS-PAGE sample buffer (Invitrogen, catalog number (Cat.No.) NP0008)+2 × Halt Phosphoric acid esterase and protease inhibitor cocktail (ThermoScientific, catalog number (Cat.No.) 1861284) in, then carry out supersound process 8-10 second with the micro tube ultrasonoscope (microtipsonicator) being set in the 5th grade respectively.In each sample, add 5 μ 110 × NuPage sample reducing agent (containing 50mMDTT), then in PCR instrument 70 DEG C of thermally denatures 10 minutes.Often kind of sample is altogether got 10 μ l and is loaded on 4-20%Tris-glycine Criterion26 hole gel (Biorad, catalog number (Cat.No.) 345-0034) each swimming lane in obtain phosphorylation mu2 trace and load 10 μ l to obtain mu2 trace in every swimming lane in 4-12%Bis-Tris (+MES damping fluid) NuPAGE26 hole gel (Invitrogen, catalog number (Cat.No.) WG1403BX10).In order to contrast, 2ng phosphorylation mu2 or 20ngmu2/Flag albumen are loaded in the most end hole of each gel.After SDS-PAGE, use iBlot to be transferred to by the sample on each gel on pvdf membrane and film is blocked 1 hour in TBST+5% milk, then wash 3 times with TBST and last 5-10 minute.With containing the anti-phosphorylation mu2 (1:5000 of rabbit; Manufactured by NewEnglandPeptide and on Lexicon, carry out the rabbit polyclonal antibody of affinity purifying) TBST+5%BSA detect Criterion gel, and with containing little mouse-anti Flag (1:500; Sigma, catalog number (Cat.No.) F1804) TBST+5% milk detection NuPAGE gel on the oscillator these primary antibodies being incubated overnight at 4 DEG C.
At the 4th day, wash immunoblotting with TBST and last 5-10 minute 3 times, in room temperature with containing anti-rabbit-HRP (1:2000; BioRad, catalog number (Cat.No.) 170-6515) or anti-mouse-HRP (1:2000; Biorad, catalog number (Cat.No.) 170-6516) TBST+5% milk detect 1 hour, with TBST wash last 10 minutes for 3 times and with ECL reagent (GEHealthcare, catalog number (Cat.No.) RPN2132) develop on Versadoc.Finally, install photographic camera to carry out taking pictures lasting 10 minutes with every 30 seconds and the optimal images without saturation signal (when signal is saturated, band will be high shiny red) of preserving each trace.Measure analysis is carried out to obtain density value to each band.The suppression per-cent of each sample calculates as follows: be first normalized with total Mu2 expression level, then compares with 0% and 100%.Then Excel fitting software is used to calculate IC
50value.
Claims (15)
1. formula (I) compound or pharmaceutically acceptable salt thereof
Wherein:
R
1and R
2independently selected from hydrogen, C
3-C
6cycloalkyl and C
1-C
3alkyl, wherein said C
1-C
3alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, amino, cyano group, two (C
1-C
3alkyl) amino, halogen and hydroxyl; Or
R
1and R
2be oxo together;
R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, amino, optionally replacement have C
1-C
3the C of alkyl or cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl, C
1-C
3alkyl-Y and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, aryl, cyano group, two (C
1-C
3alkyl) amino, halogen, C
1-C
3haloalkylamino, C
1-C
3haloalkylcarbonylamino, hydroxyl ,-NR
xr
yand C
3-C
8cycloalkyl, wherein said cycloalkyl optionally replaces further one, two or three are independently selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkoxy C
2-C
3alkylamino, amino, aryl, aryl C
1-C
3alkyl, halogen, C
1-C
3haloalkyl, C
1-C
3haloalkylamino and hydroxyl;
R
4be selected from hydrogen, C
1-C
3alkoxyl group, C
1-C
3alkoxycarbonyl amino, C
1-C
3alkyl, C
1-C
3alkylamino, C
1-C
3alkyl-carbonyl-amino, amino, arylamino, aryl-amino-carbonyl, C
3-C
6cycloalkyl amino, C
3-C
6cycloalkyl amino carbonyl, C
3-C
6cycloalkyl oxy, halogen, C
1-C
3halogenated alkoxy, C
1-C
3haloalkyl, C
2-C
3haloalkylamino, C
2-c
3haloalkylcarbonylamino and hydroxyl;
R
5be selected from hydrogen, C
1-C
3alkyl, cyano group, C
3cycloalkyl and halogen;
R
xand R
ythe 3-6 ring optionally replacing and have oxo is formed together with connecting their nitrogen-atoms; And
Y is selected from
Wherein R
6be selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl and C
1-C
6alkyl-carbonyl;
N is 0,1,2 or 3;
Each R
7independently selected from hydrogen, C
1-C
6alkyl, aryl, aryl C
1-C
3alkyl, C
3-C
6cycloalkyl, halogen and C
1-C
3haloalkyl;
Each R
8independently selected from hydrogen, C
1-C
3alkoxyl group and hydroxyl; And
R
9and R
10separately for hydrogen or form oxo group together.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
9and R
10form oxo group together.
3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R
5for hydrogen.
4. the compound or pharmaceutically acceptable salt thereof of claim 3, wherein R
4be selected from hydrogen and C
1-C
3alkyl-carbonyl-amino.
5. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein R
4for hydrogen.
6. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R
1and R
2independently selected from hydrogen and C
1-C
3alkyl, or R
1and R
2be oxo together.
7. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, optionally replacement have the C of cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces has one to be selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, cyano group, two (C
1-C
3alkyl) amino, hydroxyl and-NR
xr
y; Wherein R
xand R
y5 rings optionally replacing and have oxo are formed together with connecting their nitrogen-atoms.
8. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein:
R
1and R
2independently selected from hydrogen and C
1-C
3alkyl, or R
1and R
2be oxo together;
R
3be selected from C
1-C
6alkoxyl group, C
2-C
6alkynyl, optionally replacement have the C of cyano group
3-C
6cycloalkyl, C
3-C
6cycloalkyl amino, optionally replacement have C
1-C
6the piperidyl of alkyl and C
1-C
8alkyl, wherein said C
1-C
8alkyl optionally replaces has one to be selected from following group: C
1-C
3alkoxyl group, C
1-C
3alkoxy carbonyl, amino, amino-sulfonyl, cyano group, two (C
1-C
3alkyl) amino, hydroxyl and-NR
xr
y; Wherein R
xand R
y5 rings optionally replacing and have oxo are formed together with connecting their nitrogen-atoms;
R
4be selected from hydrogen and C
1-C
3alkyl-carbonyl-amino; And
R
5for hydrogen.
9. compound or pharmaceutically acceptable salt thereof, described compound its be selected from
(R)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide;
(S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide;
(S)-2-amino-4-methyl-N-((R)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide;
(S)-2-amino-4-methyl-N-((S)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide;
(2R)-2-amino-4-methyl-N-(5-methyl-5H-chromene is [3,4-c] pyridine-8-base also) valeramide;
(R)-2-amino-4-methyl-N-((R)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide;
(R)-2-amino-4-methyl-N-((S)-5-methyl-5H-chromene also [3,4-c] pyridine-8-base) valeramide;
(R)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide;
(S)-2-amino-N-(5,5-dimethyl-5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-sec.-propyl piperidines-2-methane amide;
(S)-2-amino-4-methyl-N-(5-oxo-5H-chromene is [3,4-c] pyridine-8-base also) valeramide;
5H-chromene is [3,4-c] pyridine-8-aminocarbamic acid peopentyl ester also;
1-(5H-chromene is [3,4-c] pyridine-8-base also)-3-cyclohexyl urea;
N-(5H-chromene is [3,4-c] pyridine-8-base also) penta-4-alkynyl amide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) valeramide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-cyano group propionic acid amide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) ethanamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-methoxypropionamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-hydroxypropanamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-1-cyano group cyclopropane carboxamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-sulfamyl butyramide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-(2-oxo-pyrrolidine-1-base) propionic acid amide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) cyclohexane carboxamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) isobutyramide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-malonamide nitrile;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3,3-amide dimethyl butyrates;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-3-methylbutyryl amine;
N-(5H-chromene is [3,4-c] pyridine-8-base also) propionic acid amide;
4-((5H-chromene is [3,4-c] pyridine-8-base also) is amino)-4-oxobutyrate;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-4-methylpentanamide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) butyramide;
N-(5H-chromene is [3,4-c] pyridine-8-base also) palmitic amide;
N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-(dimethylamino) ethanamide;
N-(the bromo-5H-chromene of 9-is [3,4-c] pyridine-8-base also) valeramide;
(R)-N-(2-acetylaminohydroxyphenylarsonic acid 5H-chromene is [3,4-c] pyridine-8-base also)-2-amino-4-methylpentanamide;
(S)-2-amino-N-(5H-chromene is [3,4-c] pyridine-8-base also)-2-phenyl-acetamides; With
(S)-N
1-(5H-chromene is [3,4-c] pyridine-8-base also)-2-diphenylphosphino ethane-1,2-diamines.
10. composition, it comprises compound or pharmaceutically acceptable salt thereof and the pharmaceutical carrier of the claim 1 of survival dose.
11. suppress to connect the active method of albumen associated kinase 1 (AAK1), and it comprises makes AAK1 contact with the compound or pharmaceutically acceptable salt thereof of claim 1.
The method of 12. treatments or the disease disposed by the mediation of AAK1 activity or illness, described method comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 to the patient's drug treatment significant quantity having these needs.
The method of 13. claims 12, wherein said disease or illness are selected from alzheimer's disease, Bipolar Disorder, pain, Parkinson's disease and schizophrenia.
The method of 14. claims 13, wherein said pain is neurogenic pain.
The method of 15. claims 14, wherein said neurogenic pain is fibromyalgia or peripheral neuropathy.
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|---|---|---|---|
| US201361768051P | 2013-02-22 | 2013-02-22 | |
| US61/768,051 | 2013-02-22 | ||
| PCT/US2014/015120 WO2014130258A1 (en) | 2013-02-22 | 2014-02-06 | 5h-chromeno[3,4-c]pyridines as inhibitors of adaptor associated kinase 1 (aak1) |
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|---|---|
| CN105121445A true CN105121445A (en) | 2015-12-02 |
Family
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Country Status (5)
| Country | Link |
|---|---|
| US (1) | US9708337B2 (en) |
| EP (1) | EP2958924B1 (en) |
| JP (1) | JP2016509066A (en) |
| CN (1) | CN105121445A (en) |
| WO (1) | WO2014130258A1 (en) |
Cited By (1)
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|---|---|---|---|---|
| CN109400524A (en) * | 2018-12-13 | 2019-03-01 | 河南师范大学 | A kind of environment-friendly preparation method thereof of 3- aldehyde radical -4- chloropyridine |
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| CN105979950A (en) | 2013-10-11 | 2016-09-28 | 百时美施贵宝公司 | Pyrrolotriazine kinase inhibitors |
| MX2016012829A (en) | 2014-04-02 | 2017-01-05 | Bristol Myers Squibb Co | Biaryl kinase inhibitors. |
| US10174044B2 (en) | 2015-04-10 | 2019-01-08 | Bristol-Myers Squibb Company | Fused pyridines as kinase inhibitors |
| EP3356330B1 (en) | 2015-10-01 | 2019-11-20 | Bristol-Myers Squibb Company | Biaryl kinase inhibitors |
| CN112142655A (en) | 2015-10-01 | 2020-12-29 | 百时美施贵宝公司 | Biaryl kinase inhibitors |
| CN110283119A (en) * | 2018-04-20 | 2019-09-27 | 长沙理工大学 | A method of synthesizing complete carbon-based substituted pyridine derivative |
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| JP2016509066A (en) | 2016-03-24 |
| EP2958924B1 (en) | 2016-12-28 |
| US9708337B2 (en) | 2017-07-18 |
| US20160016967A1 (en) | 2016-01-21 |
| EP2958924A1 (en) | 2015-12-30 |
| WO2014130258A1 (en) | 2014-08-28 |
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